Permeant delivery system and methods for use thereof

ABSTRACT

Disclosed are a patch, system, and method for delivery of a permeant composition into a subject via at least one formed pathway through a biological membrane of the subject. The patch comprises a matrix, at least one hydrophilic permeant disposed within the matrix, wherein at least a portion of the permeant can dissolve in biological moisture received from the subject, and at least one permeability enhancer disposed within the matrix. Also disclosed are systems and methods for delivery of a permeant composition into a subject via at least one formed pathway through a skin layer of the subject.

PRIORITY CLAIM

This application is a divisional of U.S. patent application Ser. No.14/064,868 filed Oct. 28, 2013 which is a continuation of U.S. patentapplication Ser. No. 12/893,477 filed Sep. 29, 2010 which is acontinuation of PCT/US2009/039045 filed Mar. 31, 2009 which claims thebenefit of U.S. Provisional Patent Application Ser. No. 61/040,744 filedMar. 31, 2008, the contents of which are hereby incorporated byreference in its entirety. This application also claims the benefit ofU.S. Provisional Patent Application Ser. No. 61/133,101 filed Jun. 25,2008, the contents of which are hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates generally to the field of transdermalpermeant delivery and more specifically to devices, systems and methodsfor using the same.

BACKGROUND OF THE INVENTION

Transdermal drug delivery systems have been marketed for a variety oftherapeutic indications over the past 20 years. Typically, transdermaldelivery systems are fabricated as multilayered polymeric laminates inwhich a drug reservoir or a drug-polymer matrix is sandwiched betweentwo polymeric layers: an outer impervious backing layer that creates anocclusive environment and prevents the loss of drug through the backingsurface and an inner polymeric layer that functions as an adhesiveand/or rate-controlling membrane. In the case of a drug reservoirdesign, the reservoir is sandwiched between the backing and a ratecontrolling membrane. The drug releases only through therate-controlling membrane, which can be microporous or nonporous. In thedrug reservoir compartment, the drug can be in the form of a solution,suspension, or gel or dispersed in a solid polymer matrix. On the outersurface of the polymeric membrane a thin layer of drug-compatible,hypoallergenic adhesive polymer may be applied.

In the case of the drug matrix design, there are two types, thedrug-in-adhesive system and the matrix dispersion system. In thedrug-in-adhesive system, the drug reservoir is formed by dispersing thedrug in an adhesive polymer and then spreading the medicated polymeradhesive by solvent casting or by melting the adhesive (in the case ofhot-melt adhesives) onto an impervious backing layer. On top of thereservoir, layers of unmedicated adhesive polymer are applied. In thecase of the matrix dispersion system, the drug is dispersedhomogeneously in a hydrophilic or lipophilic polymer matrix and fixedonto a drug-impermeable backing layer by solvent casting or extrusion.Instead of applying the adhesive on the face of the drug reservoir, itis applied to form a peripheral adhesive.

Most conventional transdermal products contain small molecule drugs(<500 Daltons) that are lipophilic in nature, allowing them to dissolveinto and diffuse through the lipid bilayers of the outer layer of theskin, the stratum corneum. Most transdermal products contain thelipophilic base form of the drug, not the hydrophilic or water solublesalt form. Transdermal delivery is typically limited to small moleculesto allow a sufficient flux into the body across a reasonably sized patcharea. To increase transdermal flux, chemical permeation enhancers havebeen added to transdermal formulations. However, use of chemicalpermeation enhancers has not been successful in achieving a sufficientflux of a hydrophilic or water soluble drug or any molecule larger than1000 Daltons to reach therapeutic levels. Accordingly, there is a needin the art for improved methods, systems and devices for achievingtransdermal delivery of permeants to a subject at therapeutic deliveryrates.

SUMMARY OF THE INVENTION

The present invention provides devices, systems and methods for deliveryof permeants through a biological membrane of a subject.

In a first aspect, the present invention is a patch which contains amatrix, at least one hydrophilic permeant and at least one permeabilityenhancer disposed within the matrix, where at least a portion of thehydrophilic permeant can dissolve in biological moisture received fromthe subject.

In one embodiment of the present invention, the hydrophilic permeant isa bioactive agent. In a particular embodiment, the hydrophilic permeantis a protein. In another particular embodiment, the hydrophilic permeantis a small molecule. In one embodiment, the hydrophilic permeant isselected from exenatide, fentanyl citrate, hydromorphone or insulin.

In another embodiment of the present invention, the permeabilityenhancer is a pH control agent. In a particular embodiment, thepermeability enhancer is selected from disodium citrate, succinic acidor tris.

In yet another embodiment of the present invention, the matrix is apolymer matrix. In one embodiment, the polymer matrix contains a singlepolymer. In a particular embodiment, the polymer is selected from awater insoluble polymer or water soluble polymer. Ethylene vinyl acetateand ethyl cellulose are typical water insoluble polymers. Polyvinylalcohol is a typical water soluble polymer.

In a still further embodiment of the present invention, the polymermatrix contains two or more polymers. In one embodiment, the two or morepolymers are selected from water insoluble polymers, water solublepolymers or combinations thereof. In a particular embodiment, thepolymer matrix contains ethylene vinyl acetate and ethyl cellulose. Inanother particular embodiment, the polymer matrix contains ethylenevinyl acetate and polyvinyl alcohol.

In another embodiment of the invention, the hydrophilic permeant isdelivered to the subject for an administration period ranging from about5 minutes to about 7 days. In one embodiment, the hydrophilic permeantis delivered to the subject for an administrative period of about 7days. In another embodiment, the hydrophilic permeant is delivered tothe subject for an administrative period of about 3 days. In a furtherembodiment, the hydrophilic permeant is delivered to the subject for anadministrative period ranging from about 12 to about 36 hours. In yetanother embodiment, the hydrophilic permeant is delivered to the subjectfor an administrative period of about 24 hours.

In a further embodiment of the present invention, the patch alsoincludes a solubility control agent. In one embodiment, the solubilitycontrol agent is a salt. In a particular embodiment, the solubilitycontrol agent is selected from sodium chloride or ammonium sulfate. In aspecific embodiment, the present invention is a patch for delivery ofexenatide through a biological membrane of a subject, wherein the patchincludes an polymer matrix containing exenatide and at least onepermeability enhancer, wherein at least a portion of the exenatidedissolves in biological moisture received from the subject. In aparticular embodiment, the permeability enhancer is a pH control agent.In one embodiment, the pH control agent is succinic acid. In a furtherparticular embodiment, the polymer matrix contains ethylene vinylacetate and ethyl cellulose. In a particular embodiment, exenatide isdelivered to the subject for an administrative period of from about 5hours to about 7 days. In one embodiment, exenatide is delivered to asubject of an administrative period of about 24 hours, about 3 days orabout 7 days.

In a further specific embodiment, the present invention is a patch fordelivery of insulin through a biological membrane of a subject, whereinthe patch includes an polymer matrix containing insulin and at least onepermeability enhancer, wherein at least a portion of the insulindissolves in biological moisture received from the subject. In aparticular embodiment, the permeability enhancer is a pH control agent.In a specific embodiment, the pH control agent is tris. In anotherparticular embodiment, the polymer matrix contains ethylene vinylacetate and polyvinyl alcohol. In a particular embodiment, insulin isdelivered to the subject for an administrative period of from about 5hours to about 7 days. In one embodiment, insulin is delivered to asubject of an administrative period of about 24 hours, about 3 days orabout 7 days.

According to a second aspect, the present invention is a patch whichcontains exenatide and at least one permeability enhancer. Thepermeability enhancer can be any permeability enhancer described abovewith respect to the first aspect of the invention. In a particularembodiment, the permeability enhancer is a pH control agent. In oneembodiment, the patch contains a polymer matrix, wherein the polymer maybe any polymer described above with respect to the first aspect of theinvention. In another embodiment, the patch contains a permeantreservoir. In yet another embodiment, the patch further comprises asolubility control agent, wherein the solubility control agent may beany solubility control agent described above with respect to the firstaspect of the invention. In a still further embodiment, the exenatide isdelivered to the subject for an administration period, wherein theadministration period may be any period described above with respect tothe first aspect of the invention.

According to a third aspect, the present invention is a patch whichcontains at least one permeant and at least one pH control agentselected from succinic acid or tris. The permeant may be any permeantdescribed above with respect to the first aspect of the invention. Inanother embodiment, the patch contains a polymer matrix, wherein thepolymer may be any polymer described above with respect to the firstaspect of the invention. In a still further embodiment, the patchcontains a permeant reservoir. In a still further embodiment, thepermeant is delivered to the subject for a administration period,wherein the administration period may be any period described above withrespect to the first aspect of the invention.

In one specific embodiment, the present invention is a patch whichcontains a permeant reservoir, exenatide and at least one pH controlagent selected from succinic acid or tris.

In another specific embodiment, the present invention is a patch whichcontains a permeant reservoir, insulin and a pH control agent selectedfrom succinic acid or tris.

According to a fourth aspect, the present invention is a system fordelivering a permeant through a biological membrane of a subject, whichsystem includes both a porator and a patch, wherein the patch contains amatrix and at least one hydrophilic permeant and at least onepermeability enhancer disposed within the matrix, wherein at least aportion of the hydrophilic permeant can dissolve in biological moistureprovided by the subject through one or more micropores formed by saidporator. In one embodiment, the porator is a thermal porator. In anotherembodiment, the porator is selected from a mechanical porator, a laserporator or a hydraulic porator.

The various embodiments described above with respect to first aspect ofthe present invention are also applicable to the fourth aspect of theinvention, including the hydrophilic permeant, the permeabilityenhancer, the matrix including the various polymer components, theadditional solubility control agent and the period of administration.

In a specific embodiment, the present invention is a system fordelivering exenatide through a biological membrane of a subjectincluding a porator and patch, wherein the patch includes an polymermatrix containing exenatide and at least one permeability enhancer,wherein at least a portion of the exenatide dissolves in biologicalmoisture provided by the subject and is delivered to the subject over anadministrative period ranging from about 5 minutes to about 7 days. In aparticular embodiment, the porator is a thermal porator. In anotherparticular embodiment, the permeability enhancer is a pH control agent.In one embodiment, the pH control agent is succinic acid. In anotherparticular embodiment, the polymer matrix contains ethylene vinylacetate and ethyl cellulose. In another particular embodiment, exenatideis delivered to the subject over an administration period selected fromabout 24 hours, about 3 days or about 7 days.

In another specific embodiment, the present invention is a system fordelivering insulin through a biological membrane of a subject includinga porator and patch, wherein the patch includes an polymer matrixcontaining insulin and at least one permeability enhancer, wherein atleast a portion of the insulin dissolves in biological moisture providedby the subject. In a particular embodiment, the porator is a thermalporator. In another particular embodiment, the permeability enhancer isa pH control agent. In one embodiment, the pH control agent is tris. Inanother particular embodiment, the polymer matrix contains ethylenevinyl acetate and polyvinyl alcohol. In another particular embodiment,insulin is delivered to the subject over an administration periodselected from about 24 hours, about 3 days or about 7 days.

According to a fifth aspect, the present invention is a system fordelivering exenatide through a biological membrane of a subject, whichsystem includes both a porator and a patch, wherein the patch containsexenatide and at least one permeability enhancer. The porator can be anyporators described above with respect to the fourth aspect of theinvention. In a particular embodiment, the porator is a thermal porator.selected from a mechanical porator, a laser porator or a hydraulicporator.

The various embodiments described above with respect to second aspect ofthe present invention are also applicable to the fifth aspect of theinvention, including the permeability enhancer, the matrix including thevarious polymer components, the additional solubility control agent andthe period of administration. In one embodiment, the patch contains apermeant reservoir.

According to a sixth aspect, the present invention is a system fordelivering exenatide through a biological membrane of a subject, whichsystem includes both a porator and a patch, wherein the patch containsleast one permeant and at least one pH control agent selected fromsuccinic acid or tris.

The various embodiments described above with respect to third aspect ofthe present invention are also applicable to the sixth aspect of theinvention, including the permeability enhancer, the matrix including thevarious polymer components, the additional solubility control agent andthe period of administration. In one embodiment, the patch contains apermeant reservoir.

According to a seventh aspect, the present invention is a method fordelivering a permeant through a biological membrane of a subjectcomprising the steps of forming one or more micropores in the biologicalmembrane and placing a patch in physical contact with the one or moremicropores to allow for delivery of the permeant, wherein the patchcontains a polymer matrix and at least one hydrophilic permeant and atleast one permeability enhancer disposed within the matrix, wherein atleast a portion of the hydrophilic permeant can dissolve in biologicalmoisture provided by the subject through one or more micropores formedby said porator. In one embodiment, the one or more micropores areformed by a thermal poration device. In another embodiment, the one ormore micropores are formed by a device selected from a mechanicalpuncture device, a laser ablation device or a hydraulic pressure device.In a particular embodiment, the micropores are formed by a heatconducting element placed in substantial physical contact with abiological membrane to deliver sufficient energy to the biologicalmembrane to thermally ablate the biological membrane.

The various embodiments described above with respect to first, secondand third aspects of the present invention are also applicable to theseventh aspect of the invention, including the permeant, thepermeability enhancer, the matrix including the various polymercomponents, the permeant reservoir, the additional solubility controlagent and the period of administration.

Additional aspects of the invention will be set forth, in part, in thedetailed description, figures and any claims which follow, and in partwill be derived from the detailed description, or can be learned bypractice of the invention. It is to be understood that both theforegoing general description and the following detailed description areexemplary and explanatory only and are not restrictive of the inventionas disclosed.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate certain aspects of the instantinvention and together with the description, serve to explain, withoutlimitation, the principles of the invention.

FIG. 1 illustrates a side view of a permeant delivery patch according toone aspect of the present invention.

FIG. 2 illustrates a side view of a permeant delivery patch according toone aspect of the present invention where the delivery patch comprisesan enhanced surface area provided by perforations.

FIG. 3 illustrates a side view of a permeant delivery patch according toone aspect of the present invention where the reservoir or matrixcomprises a plurality of delivery reservoirs or matrices positioned in astacked arrangement.

FIG. 4 illustrates an exemplary transdermal permeant delivery patchaccording to one aspect of the present invention.

FIG. 5 illustrates a schematic diagram of an electro-osmotic pumpassembly according to one aspect of the present invention.

FIG. 6 illustrates an exemplary transdermal permeant delivery patchaccording to one aspect of the present invention where the patchassembly further comprises a first, second and third electrode assembly.

FIG. 7 is a chart reporting exemplary in vitro release kinetics for apermeant delivery reservoir of the present invention.

FIG. 8 is a chart reporting exemplary pharmacokinetic profile data for apermeant delivery reservoir or matrix according to one aspect of thepresent invention.

FIG. 9 reports the effects of changes in the polymer and fentanylcitrate loading on serum drug concentrations in the hairless rat forpermeant delivery reservoirs according to the present invention.

FIG. 10 reports fentanyl serum concentrations in the hairless rat afterapplication of placebo or drug-containing films.

FIG. 11 is a chart demonstrating the effect of adding polyvinyl alcohol(PVA), a water-soluble polymer, to an insulin formulation containingtris as a permeability enhancer.

FIG. 12 is a chart demonstrating the effect of adding ethyl cellulose(EC), a water-insoluble polymer to an insulin formulation containingtris as a permeability enhancer.

FIG. 13 is a chart demonstrating the effect of various permeabilityenhancers on exenatide delivery in the hairless rat.

FIG. 14 is a chart demonstrating the effect of succinic acid (SA) andethyl cellulose (EC) in a formulation designed to achieve extendeddelivery of exenatide over 24 hours.

FIG. 15 shows the effect of ethyl cellulose to control exenatide releasefrom succinic acid and disodium citrate films.

FIG. 16 is a chart demonstrating the effect of permeability enhancercomposition on the in vitro release of exenatide from exenatide filmscontaining ethylene vinyl acetate (EVA) and the permeability enhancersof interest.

FIG. 17 shows the effect of permeability enhancer identity on themaintenance of pore permeability.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be understood more readily by reference to thefollowing detailed description, examples, and claims, and their previousand following description.

Before the present compositions, devices, systems, and/or methods aredisclosed and described, it is to be understood that this invention isnot limited to the specific articles, devices, systems, and/or methodsdisclosed unless otherwise specified. It is also to be understood thatthe terminology used herein is for the purpose of describing particularaspects only and is not intended to be limiting.

The following description of the invention is provided as an enablingteaching of the invention in its best, currently known embodiment. Thoseskilled in the relevant art will recognize that many changes can be madeto the embodiments described, while still obtaining the beneficialresults of the present invention. It will also be apparent that some ofthe desired benefits of the present invention can be obtained byselecting some of the features of the present invention withoututilizing other features. Accordingly, those who work in the art willrecognize that many modifications and adaptations to the presentinvention are possible and can even be desirable in certaincircumstances and are a part of the present invention. Thus, thefollowing description is provided as illustrative of the principles ofthe present invention and not in limitation thereof.

As used herein, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to a patch comprising a “bioactive agent” includesaspects having two or more bioactive agents unless the context clearlyindicates otherwise. Ranges can be expressed herein as from “about” oneparticular value, and/or to

“about” another particular value. When such a range is expressed,another aspect includes from the one particular value and/or to theother particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “approximately” or “about,” itwill be understood that the particular value forms another aspect. Itshould also be understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint.

As used herein, the terms “optional” or “optionally” mean that thesubsequently described event or circumstance may or may not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, a “weight percent” or “percent by weight” of acomponent, unless specifically stated to the contrary, is based on thetotal weight of the formulation or composition in which the component isincluded. As used herein, the term or phrase “effective,” “effectiveamount,” or

“conditions effective to” refers to such amount or condition that iscapable of performing the function or property for which an effectiveamount is expressed. As will be pointed out below, the exact amount orparticular condition required will vary from one embodiment to another,depending on recognized variables such as the materials employed and theprocessing conditions observed. Thus, it is not always possible tospecify an exact “effective amount” or “condition effective to.”However, it should be understood that an appropriate effective amount oreffective condition will be readily determined by one of ordinary skillin the art using only routine experimentation. As used herein, a“therapeutic amount” or a “therapeutically effective amount” of apermeant refers to an amount of permeant capable of providing a desiredresult. The desired result can be expected, unexpected, or even anunintended consequence of the administration of the permeant.

As used herein, the term “patch”, in non-limiting examples, may includetraditional drug reservoir or drug matrix patches or any other type ofpatch suitable for use in transdermal drug delivery techniques. In oneembodiment of a drug reservoir design, the reservoir may be sandwichedbetween a backing and a rate controlling membrane. The drug releasesonly through the rate-controlling membrane, which can be microporous ornonporous. In the drug reservoir compartment, the drug can be in a formsuch as, but not limited to, a solution, suspension, or gel or dispersedin a solid framework. On the outer surface of the membrane a thin layerof drug-compatible, hypoallergenic adhesive polymer may be optionallyapplied. In one embodiment of the drug matrix design, both commonlyknown types, the drug-in-adhesive system and the matrix dispersionsystem are to be included. In one embodiment of the drug-in-adhesivesystem, the drug reservoir may be formed by dispersing the drug in anadhesive polymer and then spreading the medicated polymer adhesive bysolvent casting or by melting the adhesive (in the case of hot-meltadhesives) onto an impervious backing layer. On top of the reservoir,layers of unmedicated adhesive polymer may be applied. In one embodimentof the matrix dispersion system, the drug is dispersed homogeneously ina hydrophilic or lipophilic polymer matrix and fixed onto adrug-impermeable backing layer. In another embodiment, instead ofapplying the adhesive on the face of the drug reservoir, it is appliedto form a peripheral adhesive. All forms of patches that can be placedon the skin, including the above traditional drug reservoir and drugmatrix style patches, are to be included as embodiments of the presentinvention.

As used herein, the term “hydrophilic permeant” refers to a permeanthaving an affinity for moisture. In one aspect, the moisture can bepresent in or provided by subcutaneous fluid. The subcutaneous fluid canbe intracellular and/or extracellular fluid. In one aspect, ahydrophilic permeant can be at least substantially water-soluble suchthat once contacted with a water or moisture source, such assubcutaneous fluid, the hydrophilic permeant at least substantiallydissolves in the subcutaneous fluid. In another aspect, the hydrophilicpermeant may not substantially dissolve in the subcutaneous fluid butrather may form a suspension of particulate hydrophilic permeant in thesubcutaneous fluid. As further used herein, hydrophilic permeantcomposition can include one or more hydrophilic permeants as describedherein.

As used herein, a “subcutaneous fluid” or “biological moisture” caninclude, without limitation, moisture, plasma, blood, one or moreproteins, interstitial fluid, skin tissue fluid, fluid from any of thelayers of the skin, perspiration, serum, lymphatic fluid, and/or anycombination of two or more thereof. In one aspect, a subcutaneous fluidaccording to the instant invention is a moisture source that includeswater. As used herein, the term “non-biodegradable” refers to amaterial, compound or composition, which, does not substantiallydegrade, dissolve, or erode when contacted by subcutaneous fluid. In oneaspect, a non-biodegradable material, compound or composition can be asubstantially water-insoluble material, compound, or composition. Asused herein, the term “permeant utilization” refers to the percentage ofthe initial permeant content disposed within a permeant delivery patchthat is transdermally delivered from patch into a subject during apredetermined permeant administration period.

As used herein, a “subject” refers to any living organism having atleast one biological membrane through which fluid can be obtained. Inone aspect, an exemplary biological membrane can be at least one skinlayer through which subcutaneous fluid can be obtained. For example, inone aspect a subject can be a plant. Alternatively, in another aspect,the subject can be an animal. In one aspect the animal can be mammalian.In an alternative aspect the animal can be non-mammalian. The animal canalso be a cold-blooded animal, such as a fish, a reptile, or anamphibian. Alternatively, the animal can be a warm-blooded animal, suchas a human, a farm animal, a domestic animal, or even a laboratoryanimal. Accordingly, it should be understood that the present inventionis not limited to its use in connection with any one particular subjector group of subjects. As used herein, a “biological membrane” includesan enclosing or separating layer that acts as a barrier within or arounda cell. In some aspects it can be a lipid bylayer comprised oflipid-class molecules and occasional intertwined proteins. Biologicalmembranes as used herein can also define enclosed spaces or compartmentsin which cells can maintain a chemical or biochemical environment thatdiffers from the environment outside of the space or compartment. Insome aspects, the biological membrane can be a selectively-permeablestructure, whereby the size, charge, and other chemical properties ofthe atoms and molecules attempting to cross it will determine whetherthey are capable of doing so. In one aspect, the biological membrane canbe a mucosal membrane. Exemplary mucosal membranes can include, but arenot limited to, oral, gingival, gastrointestinal, cervical, vaginal,intrarectal, intranasal, buccal, and ocular membranes. In anotheraspect, the biological membrane can be a skin layer.

As used herein, a “skin layer” can be any one or more epidermal layersof a subject. For example, in one aspect, a skin layer includes theoutermost layer of the skin, i.e., the stratum corneum. In analternative aspect, a skin layer can include one or more layers of theepidermis beneath the stratum corneum, commonly identified as stratumgranulosum, stratum spinosum (stratum malpighii), and stratum basale(stratum germinativum) layers. It will be appreciated by one of ordinaryskill in the art that there is essentially little or no resistance totransport or to absorption of a permeant through the layers of theepidermis underneath the stratum corneum. Therefore, in one aspect ofthe present invention, an at least one formed pathway in a skin layer ofa subject is a pathway in the stratum corneum layer of a subject.

As used herein, “enhancer,” “chemical enhancer”, “penetration enhancer,”“permeation enhancer,” “permeability enhancer”, and the like include allenhancers that increase the flux of a permeant, analyte, or othermolecule across the biological membrane, or within the tissue fluid. Allcell envelope disordering compounds and solvents and any other chemicalenhancement agents are intended to be included. Additionally, pH controlagents, solubility control agents (including ionic strength controlagents, salting-out agents, and water soluble polymers) and fillers areintended to be included. Additionally, all active force enhancertechnologies including, but not limited to, the application of sonicenergy, mechanical suction, pressure, or local deformation of thetissues, sonophoresis, iontophoresis or electroporation are included. Insome cases, the hydrophilic permeant can also act concurrently (with itsrole as permeant) or separately as a permeability enhancer. One or moreenhancer technologies may be combined sequentially or simultaneously.For example, a chemical enhancer may first be applied to permealize thecapillary wall and then an iontophoretic or sonic energy field may beapplied to actively drive a permeant into those tissues surrounding andcomprising the capillary bed. As used herein, “transdermal” or“percutaneous” includes the passage of a permeant into and through oneor more skin layers to achieve effective therapeutic blood levels orlocal tissue levels of a permeant.

As used herein, a “formed opening”, “artificial opening”, or “micropore”means any physical breach of the biological membrane of a suitable sizefor delivering or extracting fluid there through. “Formed opening,”“artificial opening,” “micropore,” thus refers to a small hole, openingor crevice created to a desired depth in or through a biologicalmembrane. In one embodiment, the term micropore refers to the result ofany skin abrading technology that results in biological fluid productionto the skin surface. In one embodiment, the opening may be formed viathe conduction of thermal energy as described in U.S. Pat. Nos.5,885,211 and 7,141,034, the teachings of which are incorporated hereinby reference, or through a mechanical process, through a pyrotechnicprocess, or through use of radio frequency ablation. In some aspects,the size of the hole or pore can for example be approximately 1-1000,5-700, 10-500, 50-300, 100-250, 50-100, or 70-90 microns in diameter.The hole or pore may be any shape, for example, cylinder, slit, hole,square, trough, crater, and the like. It is to be understood that theterm micropore is used in the singular form for simplicity, but that thedevices, systems, and methods may form an array of multiple openings orpores. As used herein, “poration”, “microporation”, or any such similarterm means the formation of a small hole or crevice (subsequently alsoreferred to as a “micropore”) in or through the tissue or biologicalmembrane, such as skin or mucous membrane, or the outer layer of anorganism to lessen the barrier properties of this biological membranefor the passage of at least one permeant from one side of the biologicalmembrane to the other for select purposes. Preferably the hole or

“micropore” so formed is approximately 1-1000 microns in diameter andextends into the biological membrane sufficiently to break the barrierproperties of the stratum corneum without adversely affecting theunderlying tissues. In other embodiments, the hole or micropore soformed is approximately 1-1000, 5-700, 10-500, 50-300, 100-250, 50-100,or 70-90 microns in diameter. It is to be understood that the term“micropore” is used in the singular form for simplicity, but that thedevice of the present invention may form multiple artificial openings.Poration could reduce the barrier properties of a biological membraneinto the body for selected purposes, or for certain medical or surgicalprocedures. The microporation process referred to herein isdistinguished from the openings formed by electroporation principally bythe typical minimum dimensions of the micropores which are usually nosmaller than about 1 micron across and usually at least about 1 micronin depth, whereas the openings formed with electroporation are typicallyonly a few nanometers in any dimension. Nevertheless, electroporation isuseful to facilitate uptake of selected permeants by the targetedtissues beneath the outer layers of an organism after the permeant haspassed through the micropores into these deeper layers of tissue. Forthe purposes of this application, “poration” and “microporation” areused interchangeably.

A “microporator” or “porator” is a component for a microporation devicecapable of microporation. Examples of a microporator or porator include,but are not limited to: thermal poration devices including devices withone or more filaments capable of conductively delivering thermal energyvia direct contact to a biological membrane to cause the ablation ofsome portion of the membrane deep enough to form a micropore, heatconducting elements placed in substantial physical contact with abiological membrane to deliver sufficient energy to the biologicalmembrane to thermally ablate said biological membrane, and opticallyheated topical dye/absorber layers; mechanical ablation devicesincluding electromechanical actuators, microlancets, and an array ofsolid or hollow microneedles or lancets; radiofrequency ablators, sonicenergy ablators; laser ablation systems; hydraulic puncture devicesincluding high-pressure fluid jet puncturers; techniques using physicalabrasion of the skin surface; dermal ballistic delivery devices; and thelike. A Thin Film Tissue Interface as described in U.S. Pat. No.7,141,034, the entirety of which is incorporated by reference, is afurther example of a porator. As used herein, “microporator” and“porator” are used interchangeably. “Thin Film Tissue Interface” or“TFTI” is used to describe a device that creates micropores usingthermal energy produced by the passage of electrical current throughresistive elements and methods of manufacturing and functional operationof the TFTI devices. TFTI devices create one or more micropores on awide range of biological membranes. TFTIs have applications that includethermal microporation of human skin for the enhancement of analytemonitoring and delivery of permeants such as a therapeutic drug or atattoo dye. TFTIs are characterized by their ability to rapidly andefficiently create a pattern or array of micropores on the surface of abiological membrane. The pattern may be any geometric spacing ofmicropores with various possible pore densities. In one embodiment, thepore density is as high as one pore every 0.2 square mm and poredensities may cover a total porated area ranging from a few squaremillimeters to greater than several hundred square centimeters,including 0.005-800, 0.01-500, 0.1-500, 1-300, 10-200, 25-100, and 50-75square centimeters. TFTI devices are designed to be thin, flexible,conformable structures that may form an interface between the biologicalmembrane and a controller.

Alternatively, the TFTI may be integrated with the controller itself andthis integrated device may contact the biological membrane. Thecontroller portion supplies each poration element or electrode or otheractive component such as a piezo-transducer in the TFTI with therequired electrical signal to effect the poration or other function ofthe TFTI such as, but not limited to, iontophoresis, sonophoresis,electroporation, or impedance measurement of the contacted tissue. TFTIsare flexible and may be able to conform to the shape of the targetedbiological membranes. The TFTIs are fabricated to be very thin, light inweight, and may be used separately from a patch or in an integratedfashion and are also connected to the controller or current sourcethrough an umbilical cable to allow a more user friendly configuration.When one or more controllable active additional flux enhancementfeatures are incorporated into the TFTI, such as, but not limited to,pressure modulation, mechanical manipulation, iontophoresis,electro-osmosis, sonophoresis or electroporation, the activation of thisadditional flux control feature could be controlled by the remotecontroller module either in a preprogrammed fashion, a user controlledfashion via inputs to the controller, or in an automatic, closed loopfashion wherein the rate of infusion of a permeant is modulated as afunction of the measured level of a selected analyte within or othermeasurable property of the organism. The other measurable property couldinclude heart rate, blood pressure, temperature, respiration, and skinsurface conductivity. For example, in one embodiment, it is useful tocontrol the rate of insulin infusion based on the real-time measurementof glucose concentrations in the interstitial fluid or serum of anorganism. In another embodiment, it is desirable with some therapeuticcompounds, particularly those with narrower therapeutic windows definingwhat an effective drug level is versus when the negative side effectsbecome too intolerable, to modulate the infusion rates based on themeasurable levels of this compound within the organism, thereby allowinga very accurate, and self adaptive method for achieving and maintainingthe drug concentration within a desired therapeutic window regardless ofpatient body mass or metabolism. In the design and manufacture of theTFTI, many of the electrically conductive traces comprising the TFTIcould be used to serve multiple functions. For example, the traces usedto deliver the short pulses of current to the resistive porationelements to induce the thermal cycling, could also be used for eitherclosed loop feedback control of the microporation or to incorporateenhancement as electrodes for an iontophoretic or electroporationprocess, carried out after the micropores have been formed.

As used herein, “iontophoresis” refers to the application of an externalelectric field to the tissue surface through the use of two or moreelectrodes and delivery of an ionized form of drug or an un-ionized drugcarried with the water flux associated with ion transport(electro-osmosis) into the tissue or the similar extraction of abiological fluid or analyte.

As used herein, “electroporation” refers to the creation throughelectric current flow of openings in cell walls that are orders ofmagnitude smaller than micropores. The openings formed withelectroporation are typically only a few nanometers, for example 1-10nanometers, in any dimension. In one example, electroporation is usefulto facilitate cellular uptake of selected permeants by the targetedtissues beneath the outer layers of an organism after the permeant haspassed through the micropores into these deeper layers of tissue.

As used herein, “sonophoresis” or “sonification” refers to sonic energy,which may include frequencies normally described as ultrasonic,generated by vibrating a piezoelectric crystal or otherelectromechanical element by passing an alternating current through thematerial. The use of sonic energy to increase the permeability of theskin to drug molecules has been termed sonophoresis or phonophoresis.

The present invention is based, in part, upon new approaches totransdermal delivery that have been developed through increasing thepermeability of a biological membrane. According to some aspects, thepermeability can be achieved by physically altering the membrane via theformation of artificial openings or pathways through at least one layerof the membrane. These openings can provide fluid communication oraccess through the membrane. For example, where the biological membraneis the stratum corneum skin layer, the formed openings can provideaccess or fluid communication to the hydrated, living layers of theepidermal and dermal skin tissues beneath the stratum corneum layer. Tothat end, these openings, or micropores, can be viewed as aqueouschannels or formed pathways, through which not only permeant candiffuse, but fluid can be pumped, micro-particles can be delivered, orfluid from within the subject can exude to the surface of the skin. Byutilizing the bi-directional properties of fluid flow and micropores ofthis type the present invention provides, in one aspect, improveddevices, systems and methods of transdermal permeant delivery asdescribed in detail below.

According to aspects of the invention, a patch or a system including thepatch plus a porator is provided for causing flux of a bioactive agentinto a subject via at least one formed pathway through a biologicalmembrane of the subject. The patch includes a matrix. The matrix has asurface adapted for contacting a biological membrane and the matrix isfurther adapted to absorb or otherwise receive biological moisture fromat least one formed pathway through the biological membrane. A permeantcomposition is disposed within the matrix. The permeant compositionincludes an undissolved hydrophilic permeant, where said hydrophilicpermeant may include at least one bioactive agent, and further includesat least one permeability enhancer like a pH control agent. In oneembodiment, the hydrophilic permeant of the permeant composition isdelivered into the subject. In another embodiment, both the hydrophilicpermeant and the permeability enhancer of the permeant composition aredelivered into the subject. In some aspects, the bioactive agent canalso provide the functionality of the at least one permeabilityenhancer.

In one embodiment, the permeant composition can come in contact withbiological moisture, such as subcutaneous fluid, when the bottom surfaceof the patch is positioned in fluid communication with the at least oneformed pathway through the biological membrane of a subject. In anotherembodiment, at least a portion of the undissolved hydrophilic permeant,and in some instances, at least a portion of the permeability enhanceras well, can dissolve in or form a suspension in the contactedbiological moisture from the subject. Not to be limited by thisexplanation, in one embodiment it is believed that once an effectiveamount of moisture has come into contact with the permeant compositionin the matrix, the fluid subsequently provides a diffusion path fordelivering at least a portion of the permeant back through thebiological membrane into the subject. In another aspect and withoutlimitation, the permeant composition can have an affinity forsubcutaneous fluid such that at least a portion of the permeantcomposition can draw an effective amount of subcutaneous fluid from thesubject when the bottom surface of the patch is positioned in fluidcommunication with the at least one formed pathway through the skinlayer of a subject.

In one embodiment, the matrix has a surface adapted for contacting abiological membrane and is further adapted to absorb or otherwisereceive biological moisture from at least one formed pathway through thebiological membrane when the patch is positioned in fluid communicationwith at least one formed pathway. The matrix can include at least onepolymer and can include two or more polymers. The polymer or polymersmay be water soluble or water insoluble polymers. A single matrix mayinclude both water soluble and water insoluble polymers. Non-limitingexamples of water soluble polymers include polyethylene glycol (PEG orPEO or POE), polyvinyl alcohol (PVA or PVOH), and polyvinylpyrrolidone(PVP). Non-limiting examples of water insoluble polymers includeethylene vinyl acetate (EVA) and ethyl cellulose (EC). The matrixmaterial can, in an exemplary non-limiting aspect, account forapproximately 1 weight % to approximately 99 weight % of the patch,including additional amounts of about 25 weight %, about 30 weight %,about 35 weight %, about 40 weight %, about 45 weight %, about 50 weight%, about 55 weight %, about 60 weight %, about 65 weight %, about 70weight %, about 75 weight % and about 80 weight % of the patch.Additionally, the matrix material can account for any amount in anyrange of weight percentages derived from these values. For example, inexemplary non-limiting aspects, the matrix material can be in the rangeof from about 1 to about 60 weight % of the patch, about 20 to about 60weight % of the patch, about 20 to about 40 weight % of the patch, oreven about 1 to about 40 weight % of the patch.

According to aspects of the invention, the matrix can include a waterinsoluble polymeric material or combination of polymeric materials. Forexample and without limitation, in one aspect, the matrix can include anethylene vinyl acetate (EVA) copolymer, ethyl cellulose (EC),polyethylene, polyethyl acrylate, and copolymers of ethylene and ethylacrylate and any combination thereof. In one aspect, the matrix caninclude an ethylene vinyl acetate co-polymer having a relativepercentage of vinyl acetate in the range of from 0% to approximately60%, including additional vinyl acetate percentages as approximately 0%,1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% and 60% and anyrange of percentages derived from these values. In still another aspect,the ethylene vinyl acetate co-polymer includes approximately 40% vinylacetate.

As summarized above, the permeant composition includes at least onehydrophilic permeant, wherein the hydrophilic permeant can include atleast one bioactive agent, and at least one permeability enhancer suchas, but not limited to, a pH control agent. In some embodiments, thehydrophilic permeant can concurrently (with its role as permeant) orseparately function as a permeability enhancer. In addition, thepermeant composition can optionally include one or more additivessuitable for administration. For example, the permeant can optionallyfurther comprise a solubility control agent, a filler (which may bereferred to as a biocompatible filler in some cases), or any otherconventionally known substance suitable for providing or enhancing adesired transdermal delivery of a permeant. Examples of solubilitycontrol agents and of fillers will be described later. In one aspect,the hydrophilic permeant can account for approximately about 1 weight %to approximately about 99 weight % of the patch, including additionalamounts as about 5 weight %, about 10 weight %, about 15 weight %, about20 weight %, about 25 weight %, about 30 weight %, about 35 weight %,about 40 weight %, about 45 weight %, about 50 weight %, about 55 weight%, about 60 weight %, about 65 weight %, about 70 weight %, and about 75weight % of the patch, and including any range of weight percentagesderived from these values.

As used herein, a “bioactive agent” includes any drug, chemical, orbiological material that induces a desired biological or pharmacologicaleffect. The effect can be local, such as providing for a localanesthetic effect, or it can be systemic. Such substances include broadclasses of compounds normally delivered into the body, including throughbody surfaces and membranes, including skin. To this end, in one aspect,the bioactive agent can be a small molecule agent. In another aspect,the bioactive agent can be a macromolecular agent. In general, andwithout limitation, exemplary bioactive agents include, but are notlimited to, anti-infectives such as antibiotics and antiviral agents;analgesics and analgesic combinations; anorexics; antihelminthics;antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants;antidiabetic agents; antidiarrheals; antihistamines; antiinflammatoryagents; antimigraine preparations; antinauseants; antineoplastics;antiangiogenic drugs; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics; antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding potassium and calcium channel blockers, beta-blockers,alphablockers, and antiarrhythmics; antihypertensives; diuretics andantidiuretics; vasodilators including general coronary, peripheral, andcerebral; central nervous system stimulants; vasoconstrictors; cough andcold preparations, including decongestants; hormones such as estradioland other steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; tranquilizers; anti-fibromyalgia drugs;anti-psoriasis drugs; bone resorption inhibitors; agents that build bonestrength; agents that reduce bone fragility; anti-incontinence drugs;anti-infertility drugs; anti-acromegally drugs; anti-edema drugs;anti-obesity drugs; bone reorption inhibitors;

anesthetics; anti-anxiety drugs; sedatives; muscle relaxants;acetylcholinesterase inhibitors; ACE inhibitors; anti-coagulants;narcotics; anti-obsessional; anti-bulimic; anti-emetic; anxiolytics;NSAIDs; antirheumatics; hypothyroidism drug treatments; NMDA receptorantagonists; NMDA receptor agonists; partial NMDA receptor agonists;ADHD treatments, anti-spasmodic drugs, anti-convulsant drugs, migraineprophlaxis drugs; benign prostatic hypertrophy drugs; sedatives;opiates; pulmonary arterial hypertension drugs; hypnotics; osteoporosisdrugs; anti-inflammatory drugs; diabetic glycemic control drugs;multiple sclerosis drugs; thrombocytopenia drugs; and myeloidreconstitution drugs. According to aspects of the present invention, thebioactive agent can include one or more peptides, polypeptides,proteins, nucleic acids, or other macromolecules known to be difficultto deliver transdermally with existing conventional techniques becauseof their size and charge. Examples of macromolecules which may bedelivered in accordance with the present invention include, withoutlimitation, oligonucleotides, siRNA, RNAi, antisense molecules, triplehelix molecules, CpG oligomers, enhancer decoys, antibodies, LHRH, LHRHanalogs (such as goserelin, leuprolide, buserelin, triptorelin,gonadorelin, napharelin and leuprolide), GHRH, GHRF, insulin,insulinotropin, calcitonin, octreotide, endorphin, TRH, NT-36 (chemicalname: N-[[(s)-4-oxo-2-azetidinyl]-carbonyl]-L-histidyl-L-prolinamide),liprecin, pituitary hormones (eg, HGH, HMG, HCG, desmopressin acetate,etc), follicle luteoids, alpha-ANF, growth factor such as releasingfactor (GFRF), beta-MSH, GH, somatostatin, bradykinin, somatotropin,platelet-derived growth factor, asparaginase, bleomycin sulfate,chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin(ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor),glucagon, hirudin and hirudin analogs such as hirulog, hyaluronidase,interleukin-2, menotropins (urofollitropin (FSH) and LH), oxytocin,streptokinase, tissue plasminogen activator, urokinase, vasopressin,desmopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensinII antagonists, antidiuretic hormone agonists, antidiuretic hormoneantagonists, bradykinin antagonists, CD4, ceredase, CSI's, enkephalins,FAB fragments, IgE peptide suppressors, IGFI, neurotrophic factors,colony stimulating factors, parathyroid hormone and agonists,parathyroid hormone antagonists, prostaglandin antagonists, cytokines,Iymphokines, pentigetide, protein C, protein S, renin inhibitors,thymosin alpha-I, thrombolytics, TNF, GCSF, EPO, PTH, heparin, lowmolecular weight heparin, enoxaparin (Lovenox or Clexane), syntheticheparin, vaccines, vasopressin antagonist analogs,interferon-alpha,-beta, and -gamma, alpha-I antitrypsin (recombinant),and TGF-beta. genes; peptides; polypeptides; proteins; oligonucleotides;nucleic acids; and polysaccharides, glucagon-like peptide-1 analogues,and Amy Hn analogues.

As used herein, the term “peptide” refers to peptides of any length andincludes proteins. The terms “polypeptide” and “oligopeptide” are usedherein without any particular intended size limitation, unless aparticular size is otherwise stated. Exemplary peptides that can beutilized include, without limitation, oxytocin, vasopressin,adrenocorticotrophic hormone, epidermal growth factor, prolactin,luliberin or luteinising hormone releasing hormone, growth hormone,growth hormone releasing factor, insulin, somatostatin, glucagon,interferon, gastrin, tetragastrin, pentagastrin, urogastroine, secretin,calcitonin, enkephalins, endorphins, angiotensins, renin, bradykinin,bacitracins, polymixins, colistins, tyrocidin, gramicidines, andsynthetic analogues, modifications and pharmacologically activefragments thereof, monoclonal antibodies and soluble vaccines. It iscontemplated that the only limitation to the peptide or protein drugwhich may be utilized is one of functionality.

Examples of peptide and protein drugs that contain one or more aminogroups include, without limitation, anti-cancer agents, anti-angiogenicagents, pro-angiogenic agents, antibiotics, anti-emetic agents,antiviral agents, anti-inflammatory and analgesic agents, anestheticagents, anti-ulceratives, agents for treating hypertension, agents fortreating hypercalcemia, agents for treating hyperlipidemia, etc., eachof which has at least one primary, secondary or tertiary amine group inthe molecule, preferably, peptides, proteins or enzymes such as insulin,calcitonin, growth hormone, granulocyte colony-stimulating factor(G-CSF), erythropoietin (EPO), bone morphogenic protein (BMP),interferon, interleukin, platelet derived growth factor (PDGF), vascularendothelial growth factor (VEGF), fibroblast growth factor (FGF), nervegrowth factor (NGF), urokinase, etc. can be mentioned. Further examplesof protein drugs include, without limitation, insulin, alpha-, beta-,and gamma-interferon, human growth hormone, alpha- andbeta-I-transforming growth factor, granulocyte colony stimulating factor(G-CSF), granulocyte macrophage colony stimulating factor (G-MCSF),parathyroid hormone (PTH), PTH analogs (Teriparatide, Ostabolin-C) humanor salmon calcitonin, glucagon, somatostatin, vasoactive intestinalpeptide (VIP) and its active N-terminal fragments, LHRH analogs,endostatin, angiostatin, thrombospondin, Anakinra (IL-IRA) (Kineret),Alefacept (Amevive), Aldesleukin (Proleukin), Calcitonin (Miacalcin),Corticotropin (adrenocorticotropic hormone/Acthar), Efalizumab(Raptiva), Epoetin Alfa (Epogen), Etanercept (Enbrel), Exendin-4 orExenatide (Byetta), Filgrastim (Neupogen), Follitropins (Gonal-F),

Glatiramer Acetate (Copaxone), Human Growth Hormone (Somatropin,Norditropin, Genotropin, Nutropin), Interferon Beta Ia (Avonex, Rebif),Interferon Beta Ib (Betaseron), Menotropins (Pergonal, Repronex),Octreotide (Sandostatin), Oprelvekin (Neumega), Sagramostim (Leukine),Teriparatide (Forteo), Thyrotropin Alpha (Thyrogen), insulin, inhaledinsulin (Exubera), Insulin aspart (Novolog), Insulin glulisine (Apidra),Insulin lispro (Humalog), Isophane Insulin, Insulin detemir (Levemir),Insulin glargine (Lantus), Insulin zinc extended (Lente, Ultralente),Pramlintide acetate (Symlin), Growth hormone, somatotropin (Genotropin,Humatrope, Norditropin, NorlVitropin, Nutropin, Omnitrope, Protropin,Siazen, Serostim, Valtropin), Mecasermin (Increlex), Mecaserminrinfabate (IPlex), Factor VIII (Bioclate, Helixate, Kogenate,Recombinate, ReFacto), Factor IX (Benefix), Antithrombin III (ThrombateIII), Protein C concentrate (Ceprotin), beta-Gluco-cerebrosidase(Cerezyme, Ceredase), Alglucosidase-alpha (Myozyme), Laronidase(Aldurazyme), Idursulphase (Elaprase), Galsulphase (Naglazyme),Agalsidase-beta (Fabrazyme), alpha-1-Proteinase inhibitor (Aralast,Prolastin), Lactase (Lactaid), pancreatic enzymes (lipase, amylase,protease) (Arco-Lase, Cotazym, Creon, Donnazyme, Pancrease, Viokase,Zymase), Adenosine deaminase (Adagen), Pooled immunoglobulins (Octagam),Human albumin (Albumarc, Albumin, Albuminar, AlbuRx, Albutein,Flexbumin, Buminate, Plasbumin), Erythropoietin, Epoetin-alpha (Epogen,Procrit), Darbepoetin-alpha (Aranesp), Filgrastim (granulocyte colonystimulating factor; G-CS F) (Neupogen), Pegfilgrastim (Peg-G-CS F)(Neulasta), Sargramostim (granulocyte-macrophage colony stimulatingfactor; GM-CS F) (Leukine), Oprelvekin (interleukinl 1; IL-I 1)(Neumega), Human follicle-stimulating hormone (FSH) (Gonal-F,Follistim), Human chorionic gonadotropin (HCG) (Ovidrel), Lutropin-alpha(Luveris), Type I alpha-interferon, interferon alfacon 1 (Infergen),Interferon-alpha-2a (Roferon-A), Peglnterferon-alpha-2a (Pegasys),Interferon-alpha-2b (Intron A), Peglnterferon-alpha-2b (Peg-Intron),Interferon-alpha-n3 (Alferon N), Interferon-beta-1 a (Avonex, Rebif),Interferon-beta-lb (Betaseron), Interferon-gamma-lb (Actimmune),Aldesleukin (interleukin 2 (IL2), epidermal thymocyte activating factor;ETAF) (Proleukin), Alteplase (tissue plasminogen activator; tPA)(Activase), Reteplase (deletion mutein of tPA) (Retavase), Tenecteplase(TNKase), Urokinase (Abbokinase), Factor Vila (NovoSeven),Drotrecogin-alpha (activated protein C) (Xigris), Salmon calcitonin(Fortical, Miacalcin), Teriparatide (human parathyroid hormone residues1-34) (Forteo),

Octreotide (Sandostatin), Dibotermin-alpha (recombinant human bonemorphogenic protein 2; rhBMP2) (Infuse), Recombinant human bonemorphogenic protein 7 (rhBMP7) (Osteogenic protein 1), Histrelin acetate(gonadotropin releasing hormone; GnRH) (Supprelin LA, Vantas),Palifermin (keratinocyte growth factor; KGF) (Kepivance), Becaplermin(platelet-derived growth factor; PDGF) (Regranex), Trypsin (Granulex),Nesiritide (Natrecor), Botulinum toxin type A (Botox), Botulinum toxintype (Myoblock), Collagenase (Santyl), Human deoxyribonuclease I,dornase-alpha (Pulmozyme), Hyaluronidase (bovine (Amphadase, Hydase),ovine (Vitrase)), Hyaluronidase (recombinant human) (Hylenex), Papain(Accuzyme, Panafil), L-Asparaginase (ELSPAR), Peg-asparaginase(Oncaspar), Rasburicase (Elitek), Lepirudin (Refludan), Bivalirudin(Angiomax), Streptokinase (Streptase), Anistreplase (anisoylatedplasminogen streptokinase activator complex; APSAC) (Eminase),Bevacizumab (Avastin), Cetuximab (Erbitux), Panitumumab (Vectibix),Alemtuzumab (Campath), Rituximab (Rituxan), Trastuzumab (Herceptin),Abatacept (Orencia), Anakinra (Antril, Kineret), Adalimumab (Humira),Etanercept (Enbrel), Infliximab (Remicade), Alefacept (Amevive),Efalizumab (Raptiva), Natalizumab (Tysabri), Eculizumab (Soliris),Antithymocyte globulin (rabbit) (Thymoglobulin), Basiliximab (Simulect),Daclizumab (Zenapax), Muromonab-CD3 (Orthoclone, OKT3), Omalizumab(Xolair), Palivizumab (Synagis), Enfuvirtide (Fuzeon), Abciximab(ReoPro), Pegvisomant (Somavert), Crotalidae polyvalent immune Fab(ovine) (Crofab), Digoxin immune serum Fab (ovine) (Digifab),Ranibizumab (Lucentis), Denileukin diftitox (Ontak), Ibritumomabtiuxetan (Zevalin), Gemtuzumab ozogamicin (Mylotarg), Tositumomab(Bexxar), ¹³¹I-tositumomab (Bexxar 1-131), Hepatitis B surface antigen(Engerix, Recombivax HB), HPV vaccine (Gardasil), OspA (LYMErix),Anti-Rhesus (Rh) immunoglobulin G (Rhophylac), Recombinant purifiedprotein derivative (DPPD), Glucagon (GlucaGen), Growth hormone releasinghormone (GHRH) (Geref), Secretin (ChiRhoStim (human peptide), SecreFlo(porcine peptide)), Thyroid stimulating hormone (TSH), thyrotropin(Thyrogen), Capromab pendetide (ProstaScint), Indium-111-octreotide(OctreoScan), Satumomab pendetide (OncoScint), Arcitumomab (CEA-scan),Nofetumomab (Verluma), Apcitide (Acutect), Imciromab pentetate(Myoscint), Technetium fanolesomab (NeutroSpec), Cetrorelix acetate,oxytocin antagonists (atosiban, Barusiban), Romiplostim (NPlate),luteinizing hormone, somatostatin receptor agonists, peptidyl-prolylisomerase inhibitor (Cyclosporin A), low molecular weight heparins(Lovenox, Tinzaparin, Dalteparin, Desirudin (Iprivasc), Fondaparinux(Arixtra), Idraparinux, biotinylated Idraparinux (SSR 126517), AVE5026,SR 123781, glycoprotein Ilb/IIIa inhibitor (Eptifibatide: Integrilin,antibody abciximab, the non-peptide tirofiban), human B-type natriureticpeptide (Nesiritide: Natrecor), salmon calcitonin, arginine vasopressinreceptor 2 agonists (Desmopressin), HIV fusion inhibitors (GP41 bindingagonists: Enfuvirtide).

If desired, the bioactive agent can be present within the deliveryreservoir as an undissolved anhydrous hydrophilic salt. To that end, asused herein, “hydrophilic salt” and similar terms include, withoutlimitation, an ionic form of a bioactive agent, drug, or pharmaceuticalagent, such as sodium, potassium, ammonium, trimethamine, or othercation salts thereof, sulfate or other anion salts thereof, acidaddition salts of basic drugs, and base addition salts of acidic drugs.Illustrative examples of such salts include sodium diclofenac, sodiumcromolyn, sodium acyclovir, sodium ampicillin, sodium warfarin,ketorolac tromethamine, amiloride HCl, ephedrine HCl, loxapine HCl,thiothixene HCl, trifluoperizine HCl, naltrexone HCl, naloxone HCl,nalbuphine HCl, buspirone HCl, bupriprion HCl, phenylephrine HCl,tolazoline HCl, chlorpheniramine maleate, phenylpropanolamine HCl,clonidine HCl, dextromethorphan HBr, metoprolol succinate, metoprololtartrate, epinephrine bitartrate, ketotofin fumarate, atropine sulfate,fentanyl citrate, tramadol HCl, apomorphine sulfate, propranolol HCl,pindolol HCl, lidocaine HCl, tetracycline HCl, oxytetracycline HCl,tetracaine HCl, dibucaine HCl, terbutaline sulfate, scopolamine HBr,brompheniramine maleate and hydromorphone HCl.

In still another aspect, the bioactive agent can be a small moleculetherapeutic. Illustrative examples of such small molecule therapeuticsinclude Acitretin (Soriatane), Amitriptyline (Elavil), AlendronateSodium, Arpiprazole (Abilify), Bethanecol HCl (Urecholine),Bromocriptine (Parlodel), Bumetanide (Bumex), Bupivacaine (Marcaine),Buprenorphine (Buprenex), Buspirone (BuSpar), Cetirizine HCl, Citalopram(Celexa), Chlorazepate (Tranxene), Clomipramine HCl, Cyclobenzaprine(Flexeril), Donepezil (Aracept), Doxazosin (Cardura), Enalapril(Vasotec), Enoxaparin (Lovenox), Escitalopram (Lexapro), Felodipine(Plendil), Fentanyl (Sublimaze, Duragesic), Fluoxetine (Prozac,Sarafem), Fosinipril, Galantamine HBr (Reminyl, Razadyne ER), Glipizide(Glucotrol), Granisetron (Kytril), Haloperidol (Haldol), HydrocodoneBitartrate, Hydrocortisone acetate, Hydroxyzine HCl, Isradipine(DynaCirc), Ketorolac (Acular, Toradol), Leflunomide (Arava),Levothyroxine (Levoxyl, Levothroid, Synthroid), Lisinopril (Prinivil,Zestril), Lorazepan (Ativan), Loxapine (Loxitane), Meloxicam (Mobic),Memantine (Namemda), Methylphenidate (Ritalin, Concerta), Methimazole(Tapazole), Metoclopramide (Reglan), Metolazone (Mykrox, Zaroxolyn),Mirtazapine (Remeron), Montelukast, Nalbuphine (Nubain), Neostigmine(Prostigmin), Nortriptylene HCl, Olanzapine (Zyprexa), Ondansetron(Zofran), Oxybutynin Chloride (Ditropan XL), Oxycodone HCl, Oxymorphone(Numorphan), Palonosetron (Aloxi), Paliperidone, Paliperidone Palmitate,Paroxetine (Paxil), Pergolide (Permax), Perphenazine (Triaflon),Phenytoin Sodium, Pramipexole (Mirapex), Prochlorperazine (Compazine),Procyclidine (Kemadrin), Promethazine HCl, Propanolol HCl,

Protriptyline (Vivactil), Ramipril, Risperidone (Risperdal), Ropinirole(Requip), Rosiglitazone (Avandia), Selegiline (Eldepryl) (R-(−)-Deprenylhydrochloride), Tamsulosin (Flomax), Temazepam (Restoril),Thiethylperazine (Torecan), Tiagabine (Gabitril), Timolol, Tramadol,Treprostinil sodium (Remodulin), Tropisetron (Novaban), Wafarin sodium,ATI 5923, Zolpidem tartrate, and DPP-4 iinhibitors (sitagliptin(Januvia), vildagliptin (Galvus), Saxagliptin (BMS477118), Alogliptin(SYR-322), denagliptin (Redona), PHX1 149, TA-6666, GRC 8200/EMD 675992,MP513, PSN9301, R1579, BI 1356, PF-734200, ALS 2-0426, TS-021, AMG221,ABT-279, SK-0403, KRP-104, SSR162369, ARI2243, S 40010, PT-630, SYR-619,E3024, A-899301).

In still another aspect, the bioactive agent can be a therapeutic agentconventionally known for injection administration. Illustrative examplesof such therapeutic agents include adenosine, Fluorouracil, Alprostadil,Amikacin Sulfate, Amiodarone, Azithromycin, Bleomycin, Carboplatin,Ceftriaxone, Ciprofloxacin, Cisplatin, Dacarbazine, Daunorubicin HCl,Deferoxamine Mesylate, Desmopressin Acetate, Dexamethasone SodiumPhosphate, Dipyridamole, Doxorubicin HCl, Enalaprilat, Epirubicin HCl,Fluconazole, Fludarabine Phosphate, Flumazenil, Fosphenytoin Sodium,Granisetron HCl, Haloperidol Decanoate, Haloperidol, Idarubicin HCl,Ifosfamide, Irinotecan HCl, L-Cysteine HCl, Leucovorin Calcium,Leuprolide Acetate, Medroxyprogesterone Acetate, Mesna,Methylprednisolone Acetate, Metoclopramide, Mitoxantrone, NorepinephrineBitartrate, Octreotide Acetate, Ondansetron, ONXOL® (paclitaxel),Oxytocin, Pamidronate Disodium, Pancuronium Bromide, Promethazine HCl,Propofol, Sulfamethoxazole and Trimethoprim, Terbutaline Sulfate,Testosterone Cypionate, Tobramycin,

TOPOSAR® (Etoposide), Vecuronium Bromide, VINCASAR PFS® (VincristineSulfate), Vinorelbine Tartrate, ZANOSAR® (Streptozocin), Abraxane,Acthrel, Adensocan, Alimta, Amevive, Amikacin, Anzemet, Arimidex,Arixtra, Aromasin, Avastin, Avonex, Betaseron, BICNU, Botox, Campath,Camptosar, Casodex, CeeNu, Cerezyme, Cetrotide, Copaxone, Copegus,Cytoxan, DepoTestosterone, Dobutamine, Doxil, Eligard, Eloxatin, Elspar,Enbrel, Erbitux, Ethyol, Fabrazyme, Faslodex, Follistim, Fuzeon,Ganirelex (Antagon), Gemzar, Genotropin, Genotropin Minquick, Gleevec,Gonal-F, Herceptin, Hexalen, Humatrope, Humira, Hycamtin, Infergen,Infumorph, Intron A, Kineret, Kuvan, Lior Intra, Lucentis, LupronPediatric, Macugen, Matulane, Menopur, Mustargen, Myobloc, Nabi-HB,Neumega, Neupogen, Nexavar, Norditropin, Nutropin, Nutropin AQ, Orencia,Ovidrel, Pegasys, Peg-Intron, Pentam, Prograf, Proleukin, Pulmozyme,Rebetol, Rebif, Reclast, Refludan, Remicade, Repronex, Revlimid,Ribapak, Ribavirin, Risperdal Consta, Rituxan, Roferon-A, Saizen,Sandostatin LAR, Serostim, Sprycel, Supprelin LA, Sutent, Synagis,Synthroid, Tarceva, Tasigna, Tamoxifen, Taxotere, Temodar, Tevtropin,Thalomid, Thyrogen, Tobi, Tubersol, Tysabri, Tykerb, Velcade, Vesanoid,Vidaza, Vinblastine, Vincristine, Viread, Vistide, Vitamin K, Vivitrol,Xeloda, Zometa, Advate, Alphanate, Alphanine, Aranesp, Bebulin, Benefix,Epogen, Forteo, Fragmin, Helixate, Hemofil, Humate, Hyate, Koate,Kogenate, Leukine, Lovenox, Monoclate, Mononine, Myochrysine, Neulasta,Neumega, Novarel, Novoseven, Procrit,

Profilnine, Raptiva, Rebetron, Recombinate, Refacto, Caverject, D. H. E.45, Zofran, Bayrho D, Protropin, Delatestryl, Plenaxis, Hemofil-M,Monarc-M, Proplex T, Hyalgan, Supartz, Synvisc, Ellence, Zoladex,Pergonal, Carimmune, Gamimune N, Gammagard, Gammar, Iveegam,Panglobulin, Polygam, and Venoglobulin. The bioactive agent portion ofthe permeant composition can account for from approximately 1 weight %to approximately 99 weight % of the total patch weight, includingadditional amounts of about 5 weight %, about 10 weight %, about 15weight %, about 20 weight %, about 25 weight %, about 30 weight %, about35 weight %, about 40 weight %, about 45 weight %, about 50 weight %,about 55 weight %, about 60 weight %, about 65 weight %, about 70 weight%, and about 75 weight % of the patch. Additionally, the bioactive agentcan account for an amount in any range of weight percentages derivedfrom these values, including for example an amount in the range of fromabout 1 to about 10 weight %, about 1 to about 30 weight %, or even anamount in the range of from about 1 to about 60 weight %.

According to one aspect, the present invention is a patch which containsexenatide and at least one permeation enhancer. The permeation enhancercan be any permeation enhancer described herein. In a particularembodiment, the permeation enhancer is a pH control agent. In a specificembodiment, the pH control agent is selected from disodium citrate,succinic acid or tris. In one embodiment, the patch contains a polymermatrix, wherein the polymer may be any polymer described above withrespect to the first aspect of the invention. In another embodiment, thepatch contains a reservoir matrix. In yet another embodiment, the patchfurther comprises a solubility control agent, wherein the solubilitycontrol agent may be any solubility control agent described above withrespect to the first aspect of the invention. In a still furtherembodiment, the exenatide is delivered to the subject for a period ofadministration, wherein the period of administration may be any perioddescribed above with respect to the first aspect of the invention. In aparticular embodiment, the exenatide is delivered to a subject for aperiod of administration selected from about 24 hours, about 3 days orabout 7 days.

In one embodiment, the permeant composition disposed in the matrix caninclude a means for selectively controlling the pH of the biologicalenvironment in which at least one formed pathway through the biologicalmembrane exists, for selectively controlling the pH of biologicalmoisture received by the matrix, or a combination thereof. As notedabove, the means for controlling pH can be a pH control agent disposedin the matrix. The pH control agent can be adapted to dissolve inbiological moisture received from the subject when the surface of thematrix is positioned in fluid communication with at least one formedpathway through the biological membrane of the subject. The pH controlagent is provided in the matrix to adjust at least a portion ofcontacted biological moisture to a non-physiological pH and to maintainthe solubility of the hydrophilic permeant, which may be, for example,the bioactive agent. Further, according to some aspects, the pH controlagent is also capable of maintaining the contacted biological moistureat a non-physiological pH for a permeant administration period of atleast about 12 hours, at least about 18 hours, at least about 24 hours,at least about 3 days, or even at least about 7 days. In other aspects,a permeability enhancer may work in as little as about 1, about 3, about5, about 7, about 10, about 15, about 20, or about 30 minutes therebyincreasing the flux for several hours via a mechanism unrelated to pH.In other embodiments, bioactive agent loading in a matrix, alone, issufficient to maintain pore permeability of formed pathways in abiological membrane for extended administration periods up to and evenexceeding 12 hours, 18 hours, 24 hours, at least 3 days, and even atleast 7 days. However, this is not always true in all cases or with allbioactive agents. It has now been determined according to the methodsand devices of the present invention that the pH levels of thebiological environment in which the formed pathway is contained can beadjusted away from physiological pH levels in order to enhance or extendthe permeability of the formed pathway. Without intending to be limitedby theory, it is believed that maintaining the pH or other aspects ofthe biological environment at levels other than physiological may delayprocesses that are triggered in response to perturbation of thebiological membrane. Another possibility is that chelation plays a rolein the effectiveness of these pH control agents. It is to be noted thatalthough pH control agents are all able to control pH, pH control itselfmay not necessarily be the mechanism by which permeability enhancementoccurs. Furthermore, it is to be understood that pH control agents areonly one type of permeability enhancer, but that all permeabilityenhancers are to be considered part of this invention.

Physiological pH is conventionally known as approximately 7.4.Therefore, non-physiological pH as used herein refers to any pH valueother than 7.4, including pH values less than or equal to 7.3 or pHvalues greater than or equal to 7.5. To that end, it should beunderstood that the desired level of pH to be achieved by the presenceof the pH control agent will depend, at least in part, upon theparticular bioactive agent to be delivered. In some aspect, the pHcontrol agent can be select to obtain an acidic non-physiological pHlevel. For example, an acidic non-physiological pH can be in the rangeof from 2 to 6, including pH levels of about 3, 3.5, 4, 4.5, 5, 5.5 andany range of pH levels derived from these values. Alternatively, inother aspects, the pH control agent can be selected to obtain a basic oralkaline non-physiological pH level. For example, a basicnon-physiological pH can be in the range of from 8 to 10, including pHlevels of about 8.5, 9, or 9.5.

Exemplary and non-limiting examples of suitable pH control agentsinclude tris(riydroxymetriyl)aminometriane (TRIS), TRICINE, 4-(2-hydroxyethy I)-I-piperazineethanesulfonic acid (HEPES),N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES),2-(N-morpholino) ethanesulfonic acid (MES), imidazole,2-amino-2-methyl-1,3-propanediol (AMPD), amino acids such as Lysine,Arginine, Histidine, Aspartic acid, Glutamic acid, and Glycine;aminosugars such as glucosamine and galactosamine; uronic and aldonicacids such as glucuronic and gluconic acid; monocaroboxylic acids suchas glycolic or lactic acid, dicarboxylic acids such as tartaric,malonic, maleic, fumaric, malic, succinic acid and their monosodiumsalts or tricarboxylic acids such as citric acid and its mono, di, andtrisodium salts; inorganic salts with buffering properties such asmonosodium phosphate, monopotassium phosphate, disodium phosphate,dipotassium phosphate, trisodium phosphate, sodium bicarbonate, andsodium carbonate.

The pH control agent can be present in any amount capable of achieving adesired level of pH control as described above. For example, the pHcontrol agent portion of the permeant composition can account for fromapproximately 1 weight % to approximately 99 weight % of the total patchweight, including additional amounts of about 5 weight %, about 10weight %, about 15 weight %, about 20 weight %, about 25 weight %, about30 weight %, about 35 weight %, about 40 weight %, about 45 weight %,about 50 weight %, about 55 weight %, about 60 weight %, about 65 weight%, about 70 weight %, and about 75 weight % of the patch. Additionally,the pH control agent can account for an amount in any range of weightpercentages derived from these values, including for example an amountin the range of from about 1 to about 10 weight %, about 1 to about 30weight %, about 30 to about 60 weight %, or even an amount in the rangeof from about 1 to about 60 weight %.

According to one aspect, the present invention is a patch which containsat least one permeant and at least one pH control agent selected fromsuccinic acid or tris. The permeant may be any permeant describedherein. In a specific embodiment, the permeant is selected from insulin,hydromorphone, exenatide or fentanyl citrate. In another embodiment, thepatch contains a polymer matrix, wherein the polymer may be any polymerdescribed above with respect to the first aspect of the invention. In astill further embodiment, the patch contains a permeant reservoir. In astill further embodiment, the permeant is delivered to the subject for aperiod of administration, wherein the period of administration may beany period described above with respect to the first aspect of theinvention. In a particular embodiment, the permeant is delivered to asubject for a period of administration selected from about 24 hours,about 3 days or about 7 days.

In one embodiment, the permeant composition includes an additive whereinsaid additive can comprise a solubility control agent, a filler, orboth. The additive can include a means for selectively controlling therate at which a bioactive agent contained within a matrix is releasedfrom the matrix. The means for controlling the release rate of bioactiveagent from the matrix can be a solubility control agent capable ofcontrolling the dissolution of a bioactive agent in biological moisturereceived by the matrix. In some aspects, an exemplary solubility controlagent can include agents that selectively control pH of a solutionrelative to the isoelectric point of a particular bioactive agent.Maintaining the pH of a solution at or relatively near the isoelectricpoint of a bioactive agent can be used to minimize the solubility of aparticular bioactive agent in the medium, such as biological moisture.According to principles of equilibrium, as portions of dissolvedbioactive agent are delivered to a subject via at least one formedpathway through the biological membrane additional undissolved portionsof bioactive agent remaining in the matrix can then dissolve into thereceived biological moisture. Thus, by optimizing the desired pH of asolution relative to the isoelectric point of a bioactive agent, therate of dissolution of the bioactive agent can be selectivelycontrolled. In this manner, by controlling the rate at which portions ofthe bioactive agent are dissolved in the biological moisture, a bolus orburst delivery of bioactive agent can be prevented and extended deliveryprofiles can be achieved. To that end, it should be understood thataccording to some aspects of the invention, a pH control agent aspreviously described herein can also function as a means for selectivelycontrolling the rate at which a bioactive agent contained within amatrix is released from the matrix by controlling the rate at which atleast a portion of the bioactive agent is dissolved or suspended inbiological moisture received by the matrix. In an alternate embodiment,a solubility control agent may be used to maintain high solubility ofthe bioactive agent. In some embodiments, in order to maintain sustaineddrug delivery throughout the patch application period, release from thepatch must be controlled using a polymer or combination of polymers.

In alternative aspects, the solubility control agent can be an ionicstrength control agent, which selectively controls the ionic strength ofa solution. As one of ordinary skill in the art will appreciate, thesolubility of a particular bioactive agent in a medium such asbiological moisture can depend at least in part upon the ionic strengthof the medium itself. To that end, by increasing the ionic strength ofthe biological moisture received by the matrix, the solubility of aparticular bioactive agent can be reduced to inhibit the bolus or burstdelivery of the bioactive agent. According to principles of equilibrium,as portions of dissolved bioactive agent are delivered to a subject viathe at least one formed pathway through the biological membraneadditional undissolved portions of bioactive agent remaining in thematrix can then dissolve into the received biological moisture. In thismanner, by controlling the rate at which portions of the bioactive agentare dissolved in the biological moisture, extended delivery profiles canbe achieved.

Ionic strength controlling agents by this definition could include saltsof ionic compounds comprising of anions and cations so that the productis electrically neutral. Salt forming cations include but not limited toare as follows; sodium, potassium, magnesium, iron, calcium, ammonium orpyridinium. Anions of salts included but not limited to are as follows;acetate, carbonate, chloride, citrate, nitrate, hydroxide, phosphate orsulfate. The resultant ionic salts from combination of an anion andcation could include but not limited to are sodium citrates (mono, do ortri valent salts), potassium phosphates, sodium sulfates, ammoniumphosphate or sulfates, sodium chloride, etc.

In still further aspects, a solubility control agent can be asalting-out agent. As used herein, a salting-out agent can include anybiocompatible material, compound, or preferably a multivalent (highlywater soluble) salt that can generate a solution of a high ionicstrength corresponding to a salt concentration IM or higher. For exampleand without limitation, in one aspect the salting-out agent can compriseammonium, sodium or potassium sulfate, disodium or dipotassiumphosphate, trisodium phosphate, di or trisodium citrate, disodium saltsof dicarboxylic acids such as sodium succinate.

Salting-out agents as described in the embodiment control thedissolution rate of the bioactive agent inside the matrix. Agents suchas buffers and plasticizers could enhance or retard aqueous solubilityof an active agent. It has been discovered that some agents, when usedin water insoluble polymer matrices, can control the dissolution rate ofthe bioactive agent due to its solubility effect. Agents which retardthe aqueous solubility of an active agent will slow down the dissolutionrate of the active agent into the dissolution media.

It is to be understood that certain water soluble polymers can functionas solubility control agents. The optional solubility control agent canbe present in any amount capable of achieving a desired rate ofdissolution of a bioactive agent in the biological moisture received bythe matrix. For example, when present, the solubility control agentportion of the permeant composition can account for from approximately 1weight % to approximately 99 weight % of the total patch weight,including additional amounts about 5 weight %, about 10 weight %, about15 weight %, about 20 weight %, about 25 weight %, about 30 weight %,about 35 weight %, about 40 weight %, about 45 weight %, about 50 weight%, about 55 weight %, about 60 weight %, about 65 weight %, about 70weight %, and about 75 weight % of the patch. Additionally, thesolubility control agent can account for an amount in any range ofweight percentages derived from these values, including for example anamount in the range of from about 1 to about 10 weight %, about 1 toabout 30 weight %, about 30 to about 60 weight %, or even an amount inthe range of from about 1 to about 60 weight %.

As noted above, by controlling the rate of dissolution of bioactiveagent into the biological moisture received by or absorbed into thematrix, the burst or bolus delivery of the bioactive agent can beprevented, if this is so desired. To that end, according to aspects ofthe invention, extended delivery profiles can be accomplished byensuring a therapeutic amount of bioactive agent remains in the matrixafter specified administration periods in which the matrix has been influid communication with the at least one formed pathway of a biologicalmembrane. For example, according to some aspects, a therapeutic amountof undissolved bioactive agent can remain disposed in the matrix afterthe surface of the matrix is positioned in fluid communication with theat least one formed pathway for an administration period of at least 12hours; at least 18 hours, at least 24 hours, at least 36 hours or even 7days. As noted above, this remaining therapeutic amount can eventuallydissolve into biological moisture pursuant to the presence of thesolubility control agent. However, by virtue of a therapeutic amountremaining in the matrix beyond extended periods of time, the bolus orburst delivery can be prevented, affording the ability to achievedesired flux of the bioactive agent for extended periods of time.

It is to be noted that the present invention can also be used to improvedelivery when a bolus delivery profile is desired. In one embodiment,bioactive agents like enoxaparin and other low molecular weight heparincompounds are delivered more effectively as a bolus by use of theinvention described herein. Here, administration times may be about 5,4, 3, 2, 1 minute or less than 1 minute. In alternate embodiments,administration times may be greater than 5 minutes and even greater that12 hours.

In addition to the optional solubility control agent, the permeantcomposition can also include one or more fillers. Exemplary fillers caninclude any one or more of an excipient, hygroscopic agent, osmoticagent, anti-healing agent, anti-clotting agent, anti-inflammatory,anti-microbial agents, anti-irritant, reepitheliating inhibitory agent,nitrous oxide production inhibitory agent, melanogenesis inhibitoryagents, dosing agent, emollient, plasticizer, humectant, chelators, andthe like. The hydrophilic permeant itself can also exhibit thefunctionality of one or more fillers described above. One filler canalso exhibit the functionality of more than one filler described above.For example, and without limitation, an excipient can also function asan antiinflammatory agent and/or even a hygroscopic agent. The one ormore fillers, when present, can account for approximately 1 weight % toapproximately 99 weight % of the patch, including additional amounts asabout 5 weight %, about 10 weight %, about 15 weight %, about 20 weight%, about 25 weight %, about 30 weight %, about 35 weight %, about 40weight %, about 45 weight %, about 50 weight %, about 55 weight %, about60 weight %, and about 65 weight % of the patch, and further includingany range of weight percentages derived from these values.

As used herein, an anti-healing agent can include, for example,anti-coagulants, anti-inflammatory agents, agents that inhibit cellularmigration, re-epitheliation inhibiting agents, osmotic agents, andsalting-out agents. Suitable anticoagulants can comprise, for example,heparin, low molecular weight heparin, synthetic heparin, pentosanpolysulfate, citric acid, citrate salts, EDTA, and dextrans having amolecular weight from 2000 to 10,000 daltons. Suitable anti-inflammatoryagents can comprise, for example, hydrocortisone sodium phosphate,betamethasone sodium phosphate, and triamcinolone sodium phosphate.Suitable agents that inhibit cellular migration can comprise, forexample, laminin and/or its related peptides. As used herein, an osmoticagent can include any biocompatible material, compound, or compositionthat can generate, in solution, an osmotic pressure greater than about2000 kilopascals, or mixtures thereof. For example and withoutlimitation, in one aspect the osmotic agent can include a biologicallycompatible salt such as sodium chloride or a neutral compound such asglucose, or a zwitterionic compound such as glycine having asufficiently high concentration to generate, in solution, a desiredosmotic pressure. For example, in one aspect, an osmotic agent, insolution, can generate an osmotic pressure greater than about 2000kilopascals. In another aspect, an osmotic agent can generate an osmoticpressure greater than about 3000 kilopascals.

To this end, it should be understood that in an alternative aspect, thebioactive agent can also provide the functionality of any one or morefillers described above. For example, and without limitation, abioactive agent can also exhibit anti-healing effects as set forthabove. In particular, in one aspect, the bioactive agent can generate,in solution or suspension, an osmotic pressure greater thanapproximately 2000 kilopascals such that it is capable of inhibiting thehealing process of the at least one formed pathway through the skin of asubject.

As used herein, a hygroscopic agent is intended to include abio-compatible material, compound or composition having an affinity forsubcutaneous fluid such that when present in the permeant, it canenhance the drawing of subcutaneous fluid from the subject into thedelivery reservoir. For example, and without limitation, in one aspect asuitable hygroscopic agent that can be used according to the presentinvention is mannitol. The addition of a hygroscopic filler material mayalso serve as an attractant to fluid exuding from the treated skin,helping to bring the fluid into the reservoir and in contact with thebioactive agent, while also working to create more diffusion channelsfrom the skin surface side of the reservoir into the body of thereservoir where more bioactive agent can be accessed. Such fillermaterials should be selected so as to minimize any inhibition of thebioactive agent being delivered into the subject once solubilized and/orsuspended.

In one aspect, the filler can include glycerin, propylene glycol (PG),or a combination thereof. When incorporated as at least a portion of thefiller, glycerin and/or propylene glycol can function as one or more ofa humectant, hygroscopic agent, emollient, plasticizer, antimicrobial,skin permeation enhancer, and/or anti-irritant. Still further, it shouldbe understood that glycerin and propylene glycol can also be effectivefor use in increasing the release rate of a bioactive agent from amatrix as described herein and increasing bioactive agent utilization.When used, glycerin and/or propylene glycol are typically present in anamount in the range of from approximately greater than 0.0% by weight toapproximately 5.0 weight % of the patch, including amounts of about 0.5weight %, about 1.0 weight %, about 1.5 weight %, about 2.0 weight %,about 2.5 weight %, about 3.0 weight %, about 3.5 weight %, about 4.0weight %, about 4.5 weight %, and any range derived from theaforementioned weight percentages.

In another aspect, the filler can be selected such that the pH of thefluid it contacts is kept acidic. This can impart an inherentantimicrobial activity against a variety of microorganisms including,without limitation, bacteria, yeast, and mold. In addition, one or moreantimicrobial agents can also be added to the polymer film formulationto further enhance the antimicrobial activity of the film.

In one embodiment, an exemplary patch or system that includes a poratorand a patch according to the present invention provides a method forcausing the transdermal flux of a permeant into a subject via at leastone formed pathway through a skin layer of the subject. In one aspect,the method includes providing a subject having a transdermal permeantadministration site comprising at least one formed pathway through abiological membrane, such as a skin layer. As described above, thesubject can be any living organism having at least one biologicalmembrane capable of having a bioactive agent delivered or administeredthrough at least one pathway formed there through. Exemplary subjectscan be a mammal, such as, for example, a human subject. In analternative aspect, the subject can be non-mammalian. In still anotheraspect, the methods and systems of the present invention can be used ona plant.

It will be appreciated upon practicing the present invention thatutilizing an anhydrous reservoir design including undissolved permeantcomposition can improve the shelf stability of the product, reducing theneed for refrigeration in many cases. For example, in the case of aprotein, peptide, or vaccine antigen, the ability to store the productwithout refrigeration is an advantage, eliminating the need forrefrigeration throughout the distribution network. In the case ofvaccine patches, this is an attribute which would allow distribution ofvaccines throughout the world without the requirement of a reliable coldchain. The use of an anhydrous formulation can provide still otherbenefits, including the inherent antimicrobial activity presented by aformulation that does not contain water, and the ability to providephysically smaller reservoirs, as there is no required concentrationneeded to maintain a stable permeant solution. It is to be noted thatthe invention also provides for embodiments where an adjuvant (such as anormally non-permeant molecule as well as peptides) is co-delivered withthe antigen in the same patch as means to conveniently boost the immuneresponse. As illustrated in FIG. 1, a device according to one embodimentof the present invention includes a matrix 20 having a top surface 22and an opposed bottom surface 24. The permeant composition as describedabove is further disposed within the matrix. In one embodiment, thepermeant composition, including a hydrophilic permeant and a permeationenhancer like a pH control agent, can come in contact with biologicalmoisture when the bottom surface of the matrix is positioned in fluidcommunication with the at least one formed pathway through thebiological membrane of a subject. Once an effective amount of biologicalmoisture has come into contact with the matrix, the moisturesubsequently provides a diffusion path for delivering at least a portionof the hydrophilic permeant and, optionally, at least a portion of thepermeation enhancer back through the biological membrane into thesubject. For example, in one aspect and without limitation, the permeantcomposition can have an affinity for subcutaneous fluid such that atleast a portion of the permeant composition can draw an effective amountof subcutaneous fluid from the subject when the bottom surface of thematrix is positioned in fluid communication with at least one formedpathway through the skin layer of a subject. It will be appreciated uponpracticing the present invention that in one aspect an undissolvedhydrophilic permeant disposed within the matrix is not transdermallyactive or available for transdermal delivery until first coming incontact with subcutaneous fluid drawn from the subject. Furthermore,conventional implantable or oral delivery systems using highlywater-soluble drug forms typically experience a burst effect seen in theresulting PK profiles. However, by keeping the matrix of hydrophilicpermeant on the skin surface, and providing a matrix, hydrophilicpermeant, and a permeation enhancer like a pH control agent that canensure a specified release rate, this burst effect can be eliminated bythe permeant compositions of the instant invention. In an exemplaryaspect, the matrix can be constructed and arranged such that it has aporosity that defines a plurality of interconnected conduits wherein atleast a portion of the plurality of conduits are in communication withthe matrix bottom surface. According to this aspect, the undissolvedhydrophilic permeant, and optionally, the permeation enhancer like a pHcontrol agent can be disposed within at least a portion of the pluralityof conduits of the matrix. This exemplified matrix is thereby adapted touse biological moisture drawn through at least one formed pathwaythrough the biological membrane to dissolve or suspend at least aportion of the permeant, and optionally, the permeation enhancer like apH control agent disposed within the matrix, thereby enabling diffusionor transport of the dissolved agent(s) through the biological membraneand into the subject.

Various mechanisms of transport can affect the dispersion and movementof the permeant composition from the matrix into the skin tissues. Inone embodiment, a permeant disposed within the matrix becomes availableto the organism upon release by leaving the micro-particulate form andtypically going into solution or suspension in the surrounding tissue.Once in solution or suspension, diffusion can provide the transportmechanism for the micro-particulate permeant via the treated outerlayers and into or through the viable layers of the skin and into thesubject. As the process continues over time, the voids formed by thepermeant that leaves the patch and moves into the skin form channelspenetrating into the body of the matrix thereby providing additionalaccess to more permeant than was initially present at the surface of thematrix. Accordingly, by placing the matrix in communication with atleast one formed pathway through a skin layer of a subject, subcutaneousfluid can provide an effective amount or level of hydration to thematrix to dissolve or suspend the permeant. As such, a relatively highconcentration of permeant in solution or suspension can be provided thatis also in communication to the viable tissue layers of the skin. Again,it is to be noted that the permeation enhancer like a pH control agentcan accompany the permeant in any one, multiple, or all steps of thisprocess and all processes described through this application. By forminga patch according to the present invention, it will be appreciated thatit is possible to achieve a relatively high level of permeantutilization not heretofore realized by conventional transdermal deliverydevices, systems and methods known for transdermal permeant delivery.Conventional transdermal products rarely utilize more than approximately30-40% of the bioactive agent present within the patch. However, using aconventional residual analysis, the delivery matrices of the presentinvention can, in one aspect, provide a permeant utilization in therange of from approximately 10% to approximately 100%, including suchpermeant utilizations of about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90% and about 95%and including any range of permeant utilizations derived from thesevalues.

Additionally, it will also be appreciated upon practicing the presentinvention that a delivery matrix according to the present invention iscapable of maintaining a relatively constant, relatively high chemicalpotential driving force by continually dissolving or suspendingundissolved permeant disposed within the matrix, thus enabling suspendedor dissolved permeant in communication with at least one formed pathwayto remain at or near saturation levels for extended administrationperiods. By using a matrix as the permeant carrier, one can effectively‘fill’ the space between a plurality of formed pathways over the area ofthe treated skin site, with an inert, but effectively porous matrix,keeping the required volume of fluid to a minimum. In contrast,conventional methods and devices require a relatively larger quantity ofpermeant to create the saturation point condition in order to yield thesame osmotic driving force for the permeant to enter the skin than itdoes when the permeant is present in an undissolved anhydrous solidform. With a traditional pure liquid or gelled aqueous formulation, ittakes a much larger quantity of bioactive agent to cover the treatedskin site and yield the same saturation level driving force for thebioactive agent to enter the skin than it does when the bioactive agentis present in the solid form, without any water other than thatpresented by the body via the micropores. In one aspect, thefunctionality of the system is enabled by the aqueous channels in theskin provided by altering the outermost layers of the skin such thatthey become permeable during the wear period to a degree sufficient toallow subcutaneous fluid to exit the subject, dissolve or suspend thebioactive agent, and then allow the dissolved or suspended bioactiveagent to migrate into the body via these same aqueous channels.

The delivery matrices of the instant invention can be manufactured byany conventionally known means for providing a solid matrix having atleast one undissolved hydrophilic permeant disposed therein. Forexample, in one embodiment where the delivery device includes a polymermatrix, the polymer and hydrophilic permeant composition, furtherincluding any permeability enhancer (like a pH control agent),solubility control agent, and/or optional filler, can be dry-mixedtogether using a heated kneading mixer. If the permeant includes aplurality of components, the plurality of permeant compositioncomponents can, if desired, be premixed to ensure a homogenous permeantcomposition prior to the mixing of the permeant with the polymericmatrix material. Such permeant pre-blending, if desired, can beperformed, for example, on a conventional rotisserie mixer.

The temperature setting of the mixing system should be high enough toallow the particular polymeric material to soften such that it can bekneaded, but not so high as to induce melting of the particular permeantcomponents. Such conditions are of course dependent on the properties ofthe particular polymeric matrix material and the permeant to be disposedtherein. Accordingly, one of skill in the art will be able to readilyobtain such operating parameters without requiring undueexperimentation. The resulting heat-kneaded mixture can then processedinto individual dosage forms of the delivery device comprising, forexample, film sheets cut or otherwise configured into any desired shapesuch as a circular, elliptical, rectangular, square, or any otherdesired shape.

The permeant delivery device can also be manufactured in any desiredthickness, including thicknesses in the range of from approximately 0.01mm to approximately 30 mm, including such thicknesses as about 0.05,about 0.1, about 0.5, about 1.0, about 5.0, about 10.0, about 15.0,about 20.0, and about 25.0 or even any range of thicknesses derived fromthese values. For example, the thickness can be in the range of fromabout 0.01 mm to about 10.0 mm, or even about 0.5 mm to about 1.0 mm. Tothis end, it will be appreciated upon practicing the present inventionthat the desired thickness can, for example, depend on the particularmatrix components and/or the desired delivery parameters for a givenpermeant composition delivery device. For example, in one aspect it maybe desired to provide a thicker delivery film in order to provide alonger administration period. Accordingly, such customization andoptimization of the particular delivery device dimensions will bereadily obtained by one of skill in the art through no more than mereroutine experimentation.

In one embodiment, this processing may be accomplished by melt-pressinga quantity of the heat-kneaded admix into a substantially uniformthickness and then using a conventional die cutting method to form thefinal shape of the delivery device. Alternatively, the processing of theadmix can be achieved by extrusion of the heated admix through a diewhich forms a ribbon of substantial uniform width and thickness, fromwhich the delivery device can be cut either by chopping the ribbon intodesired lengths forming, for example, rectangular dosage forms, or diecutting the final dosage form out of the ribbon. In one embodiment,using a die cutting method on the extruded ribbon, the processingmachinery can further be configured to recycle the excess ‘edges’ of theribbon left after the die cutting procedure, back into the input feed ofthe mixing/extruding machine, thus achieving a near-zero loss processfor mixing the raw components and forming the final dosage form of thedevice. Alternatively, a cryo-milled polymeric powder could be mixedwith the permeant and optional other components until a substantiallyuniform and homogenous distribution of the permeant and polymer isachieved. The resulting mixture can then be hot or cold press formed, ormelt extruded into the final desired delivery device shape. In stillanother aspect, a conventional solvent casting process can be usedwherein the matrix material is dissolved into an organic solvent suchas, for example, methylene chloride, methyl-t-butyl ether, methyl ethylketone, ethyl acetate, propyl acetate, isopropyl acetate, ethanol,acetone or their binary/tertiary mixtures. The undissolved permeant andoptional other components can then be added to the dissolved polymericmatrix material and the resulting suspension can then poured into formshaving the desired size and shape. The solvent, such as the methylenechloride, can then be evaporated or otherwise removed to provide thepermeant delivery device.

As one of skill in the art will appreciate, the relative amounts ofbioactive agent(s), permeability enhancer(s) (like pH control agents),solubility control agent(s), filler component(s) and matrix material canall be adjusted to provide the desired flux rate of the permeant into asubject as well as the desired duration or effective administrationperiod. For example, the permeant can comprise a filler component, suchas a dosing agent, in an amount relative to a predetermined amount ofbioactive agent, which can provide a predetermined transdermal dosage ofbioactive agent. Alternatively, the permeant composition itself can bepresent in an amount and composition, relative to a predetermined amountof the solid matrix, which can provide a predetermined rate oftransdermal permeant diffusion.

In one aspect, the concentration of undissolved permeant disposed withinthe anhydrous reservoir is designed to provide the desired statisticalprobability that upon exposure to a moisture source, such as thesubcutaneous fluid obtained from the micropores in the skin, themoisture will dissolve or suspend the undissolved permeant such thataqueous channels develop into and through the matrix, progressivelyforming throughout the matrix until the required amount of permeantneeded to be delivered to the subject through the micropores has beendissolved or suspended and diffused through these channels, through themicropores and into the subject's skin. By choosing the appropriateratios, a matrix can be constructed which insures that substantially allof the permeant in the matrix will be accessible via these aqueouschannels formed by the solution front as it moves progressively furtherinto the matrix.

Further, optional solubility control agents and/or fillers can beincluded in the device to control the release rate of the bioactiveagent, modify the solubility of the bioactive agent in the skin tissues,inhibit or enhance selected physiological phenomena within the affectedtissue such as, but not limited to, boosting an immune response,inhibiting an inflammatory response, edema or erythema, maintaining aspecified pH range in the tissue, and the like. To this end, byconstructing the delivery device to provide a release rate which is morelimited than the slowest rate that the skin tissues can absorb thebioactive agent, the system can be made to be extremely repeatableregardless of inter or intra subject variability that typically affectthe bioactive agent delivery rate.

In one embodiment, the egress of the drug from the matrix can becontrolled through the addition of a variety of polymeric species. Thesepolymers may affect the porosity of the matrix, thereby limiting theavailability of interstitial fluid to the permeant or permeabilityenhancer(s) and thus offering control of permeant and/or permeabilityenhancer(s) delivery. These polymers, especially when of thewater-soluble variety, may also be able to limit the availability ofinterstitial fluid to the permeant and/or permeability enhancer(s) andthereby control their egress from the film. For example, interstitialfluid which is required for dissolution of the permeant or permeabilityenhancer(s) can be partially consumed by the dissolution of thewater-soluble polymer, thus effectively controlling delivery of theother water-soluble species. Alternatively, the dissolution of awater-soluble polymer can result in an increase in viscosity of the filmenvironment which may also act as a means to control delivery ordissolution. Alternatively, the dissolution of the polymer may result ina film environment in which the effective concentrations of the permeantor permeability enhancer(s) are lower than in the absence of dissolvedpolymer, thereby lowering the rate of delivery.

It should also be understood that the device of the present invention isnot limited to aspects comprising a single delivery patch, but furtherembodies aspects including a plurality of delivery patches. For example,as depicted in FIG. 3, in one aspect the device of the instant inventioncan include a plurality of delivery matrices or reservoirs positioned ina stacked arrangement. As illustrated, a delivery matrix or reservoir 20can comprise, for example and without limitation, three permeantdelivery matrices (or reservoirs), 20(a), 20(b) and 20(c) positioned ina stacked arrangement.

Alternatively, a device according to the present invention can include aplurality of matrices positioned in an adjacent or side-by-siderelationship. In still another aspect, a device according to the presentinvention can include a combination of a plurality of stacked matricesand a plurality of adjacent delivery matrices. By providing amultilayered plurality of delivery matrices, wherein as each layer issequentially accessed by the dissolution front, the predeterminedrelease rate can be varied over a predetermined permeant administrationperiod, thus enabling one of skill in the art to tailor the resulting PKprofile of the permeant in the subject. For example, in one aspect, aplurality of delivery matrices can be provided where at least twomatrices include different dimensional characteristics. In anotheraspect, at least two matrices can be provided, each having a differentpermeant composition deposited therein. In still another aspect, it iscontemplated that a plurality of delivery matrices can be provided whereeach of the plurality of matrices includes a different permeantcomposition. In still another aspect, a plurality of permeant deliverymatrices can be arranged to provide a predetermined pattern of pulsatilebioactive agent delivery. This can be done with a completely passivediffusion system wherein the delivery matrix is constructed with aplurality of matrix layers, some containing permeant and some not. Thus,as the solution front moves through the matrix, bioactive agent will bedelivered only during those periods where the layer that contains it isat the edge of the solution front. Customizing the bioactive agentcontent in these multiple layers provides a transdermal delivery systemwhich can adjust the influx to be optimal. For example, an insulindelivery system can be constructed to compliment the natural circadiancycles of a subject's glucose metabolism, thus varying the amount ofbioactive agent delivered over the dosing period in a programmed fashionto provide better therapy.

Additional methods for providing permeant release rate control caninclude, but are not limited to, altering the physical design of thematrix, altering the tortuosity of the diffusion paths formed as thedissolution front migrates into the matrix, the choice of anhydrouspolymer or other matrix material, or by the addition of specificrate-limiting mechanisms such as a specified membrane or layer withinthe matrix. In one embodiment, the polymer matrix can be formed with aspecified texture on the skin contact surface said texture designed toincrease the surface area of the skin contact surface. By increasing thesurface area between the matrix and the skin, the initial rate ofrelease of bioactive agent into the fluid interface between the patchand the micropores will be greater, resulting in a higher initial fluxof the bioactive agent. As the bioactive agent within the matrix nearthe textured surface is depleted, and the aqueous porosities penetratinginto the polymer matrix extend further into the matrix, the flux of thebioactive agent will slow down as the effect of the increased surfacearea becomes diminished, the further the dissolution front moves intothe body of the matrix. Exemplary surface area enhancements can include,but are not limited to, corrugations, perforations, a series of holesextending into the matrix, either partially through or all the waythrough or a combination of partial and complete holes, with thepartials all at one depth or at an assortment of depths.

Essentially, any physical forming of the matrix that modifies thesurface area exposed to the dissolving fluid presented via themicropores, could be used to tailor the flux at various time pointsduring the wear period. Some of the processes useful for forming thematrix in this manner include, but are not limited to, extrusion,stamping, casting, punching, die-cutting, rolling, melting, lasermachining, milling, etching or hobbing process, or any combinationthereof. These texturing and puncturing of the matrix in layers can beapplied to internal layers that are sandwiched between other layers aswell, not just to the layer placed on the surface of the skin. Withreference to FIG. 2, an exemplary delivery matrix comprising an enhancedbottom surface area is depicted. As shown, a delivery matrix 20(d) cancomprise a textured bottom surface 22 wherein the textured surfacecomprises a series of linear perforations 28.

It will be appreciated upon practicing the present invention that thedevices described herein can be used to transdermally deliver a permeantfor extended administration periods. To that end, a delivery matrix asdescribed herein can be used to transdermally deliver a permeant to asubject over a predetermined administration period ranging fromapproximately 5 minutes up to approximately 400 hours or more, includingadministration periods of approximately 1, 5, 10, 12, 15, 18, 20, 24,30, 36, 45, 50 minutes and approximately 1, 5, 9, 10, 12, 15, 18, 20,24, 30, 36, 45, 50, 100, 150, 200, 250, 300 and 350 hours.Alternatively, the devices of the instant invention can be used totransdermally deliver a predetermined amount of permeant during apredetermined administration period of about 5 minutes to about 1 hour,about 1 hour to about 6 hours, about 6 to about 12 hours, about 12 toabout 30 hours, about 30 to about 50 hours, about 50 to about 80 hours,about 80 to about 120 hours, and even about 120 to about 180 hours. Inother embodiments, the devices of the instant invention can be used totransdermally deliver a predetermined amount of permeant during apredetermined administration period of about 1 day, about 3 days, orabout 7 days.

To this end, while not intending to be limited by theory, in someaspects the relatively long administration periods achieved by thedevices of the present invention can be a result of the high osmoticpressure diffusion gradient resulting from maintaining the dissolved orsuspended permeant near the saturation point for extended periods oftime. It is further believed that these relatively high osmotic pressuregradients can themselves provide an anti-healing influence on the formedpathway through the opening in the skin layer of a subject furtherenhancing the ability to achieve extended administration periods. Thus,it should be appreciated that the delivery devices of the presentinvention can be constructed and arranged to deliver a predeterminedlevel of permeant over virtually any desired administration period. Anexemplary device according to one aspect of the present invention isdepicted in FIG. 4. As illustrated, the exemplary device provides atransdermal patch assembly, comprising a delivery matrix or reservoir 20as previously described herein. The delivery matrix is constructed andarranged such that it has a top surface and an opposed bottom surface. Abacking support layer 30, having an inwardly facing surface is at leastpartially connected to the top surface of the delivery matrix. In oneaspect, in order to releasably affix the delivery matrix to the skin ofa subject, the backing support layer can be sized and shaped such thatit peripherally extends beyond the delivery matrix. Further, at least aportion of the inwardly facing surface of the peripherally extendingbacking support layer can further comprise an adhesive layer 50deposited thereon. As one of skill in the art will appreciate, theadhesive layer deposited on at least a portion of the backing layerwhich extends beyond the periphery of the matrix can provide aperipheral adhesive attachment system.

Alternatively, it is also contemplated that the delivery matrix can bedesigned so as to have a skin contact surface tacky enough to releasablyadhere directly to the skin of a subject. This can minimize the totalsize of the patch and reduce the reliance on the peripheral adhesive tomaintain sufficient adhesion to adhere the patch to the skin for theduration of the patch wear period (e.g. 1, 2, 3, or 7 days). It will beappreciated upon practice of the invention disclosed herein that such amatrix can be obtained by, for example, optimizing the percentage ofpolymer, hydrophilic permeant, and/or permeability enhancer as well asthe manufacturing process parameters. Such optimization can bedetermined by one of skill in the art without the need for undueexperimentation.

The backing support layer 30 can in one aspect be at least substantiallyocclusive. Alternatively, the backing support layer can be at leastpartially semipermeable. To this end, in some cases, a semi-permeablebacking, such as for example the 3M Tegaderm® product, can provide addeduser comfort as a vapor permeable backing typically having higher usertolerance for longer wear periods. In addition, the release rate of thedrug into the skin can be controlled by controlling the rate of watertransport through the film by designing the semi-permeable backingsupport layer with a specific mean vapor transmission rate (MVTR). Inother cases, a more completely occlusive backing may be preferred inorder to ensure the maximal hydration of the matrix from subcutaneousfluid that is accessed from at least one formed pathway beneath thepatch assembly, as well as from transepidermal water loss through theintact skin surrounding and between the formed pathway(s).

Alternatively, the backing can be made totally occlusive to promotehydration of the film and thus contact with the subcutaneous fluid,while the peripheral adhesive can be made semi-permeable to allow betterwear characteristics such as better adhesion, and/or lower irritation.The patch assembly can further include a peelable protective releaselayer 40 sized and shaped to protect at least a portion of the bottomsurface of the delivery matrix from environmental elements until thedevice is to be used. In one aspect, the protective release layer can beremovably secured to at least a portion of peripherally extendingbacking support layer having the adhesive layer deposited thereon. Aswill be appreciated, the positioning of the release layer according tothis aspect not only provides protection to the bottom surface of thedelivery matrix but can further add a protective layer to the adhesivelayer deposited on the peripherally extending portion of the backingsupport layer. The patch assembly comprising the delivery matrix,backing support layer, adhesive layer and protective release layer canthen placed in an individual pouch and sealed shut.

In one embodiment, an exemplary delivery matrix according to the presentinvention provides a method for causing the transdermal flux of apermeant into a subject via at least one formed pathway through a skinlayer of the subject. In one aspect, the method comprises providing asubject having a transdermal permeant administration site comprising atleast one formed pathway through the skin layer. As used herein, thesubject can be any living organism having at least one skin layercapable of transdermal permeant administration. To this end, the subjectcan be a mammal, such as, for example, a human subject. In analternative aspect, the subject can be non-mammalian. In still anotheraspect, the methods and systems of the present invention can be used ona plant.

The transdermal permeant administration site is comprised of at leastone formed pathway though a skin layer of the subject. The pathway canbe formed by any currently known means for providing a pathway through askin layer of a subject. To that end, the skin treatment may be somemethod of forming one or more small, artificial openings, or microporesin the skin within the size range of 1-1000 microns across, includingabout 1 to about 500, about 100 to about 1000, about 200 to about 600,and about 400 to about 800 microns across and 1 to 500 microns deep,including about 1 to about 100, about 50 to about 100, about 70 to about90, about 20 to about 80, about 100 to about 400, about 200 to about300, and about 250 to about 500 microns deep which allow fluidcommunication between the bioactive agent or matrix and the viable celllayers of the skin beneath the outer most layers of the organism's skin,typically the stratum corneum in a human. These micropores can allowsubcutaneous fluid to exude through the micropores to the surface of theskin.

In exemplary aspects, and not meant to be limiting, micropores orpathways in the skin of the subject can be formed by applying thermalporation devices, mechanically puncturing the skin with micro-needles,lancets or blades, laser ablation, radiofrequency or electricalablation, electrical puncturing or ablation, and/or hydraulic jets.Creating pathways by mechanical methods includes use of projections suchas solid microneedles or “pyramids” to puncture the skin or scrapetracks or paths through the stratum corneum. The skin treatment may alsoinclude, but is not limited to, methods such as the application ofacoustic energy or sonication of the skin to increase its permeability,electroporation, tape stripping, abrasive stripping or abrasivetreatments, gas jet abrasive treatments, micro-puncturing by theapplication of high velocity inert particles to the skin via apparatussuch as those described by PowderJect Pharmaceutical PLC, chemicaltreatments, heat treatments, or mechanical treatments to make the skinsuitably permeable. Exemplary systems, devices, and methods for formingthe desired micropores are discussed in U.S. Pat. Nos. 5,885,211,6,527,716, 6,597,794, 6,611707, 6,692,456, 6,708,060, and 6,711,435 andUnited States Patent Application Nos. 2004-0220456, 2004-0039342, and2004-0039343, all of which are incorporated in their entirety herein byreference. After removal of the protective release layer, the patchassembly can then be positioned on the skin of the subject in a mannerwhich at least substantially co-locates the bottom surface of thedelivery matrix over a permeant administration site having at least oneformed pathway through a skin layer of the subject, as described hereinsuch that the permeant delivery matrix comprising an undissolvedhydrophilic permeant is in fluid communication with at least one formedpathway through the skin layer of the subject. Various methods ofsimplifying the co-location of the active area of the patch to themicroporated skin site can be incorporated into an integrated systemdesign such as, for example, a system of visual marks left after theapplication of the microporation method to allow the user to place thepatch in the correct position when these marks are used as referencepoints. These marks may be formed with markers such as, but not limitedto, a dye or ink, or even simply formed by mechanical texture leaving atemporary pattern on the skin; a fold-over co-location system whereinthe patch is temporarily attached to the poration system in a fashionwhich when the poration is accomplished and the poration system isremoved from the skin site, a small ‘hinge’ component is left behindholding the patch such that when the patch is folded over and the hingeis flexed 180 degrees, the needed co-location is ensured; a locator ringof peripheral indicators are left on the skin after the removal of theporator system which provide the needed guides for proper placement ofthe patch; a fully automated applicator system is used whichsequentially applies the poration system, removes it and then appliesthe patch in a fashion completely transparent and optionally, evenhidden, to the user; a fully integrated system is used wherein theporator component is biocompatible, is directly integrated into the skinside of the patch and is designed to allow it to be left in placeagainst the skin under the reservoir after the poration process has beaccomplished. Thus, in one embodiment, the porator is porous enough toallow the required flux of fluid from the micropores to enter the matrixand the dissolved or suspended bioactive agent from the matrix, backaround/across the porator and into the micropores.

In one embodiment, the permeant delivery matrix is maintained in fluidcommunication with the at least one formed pathway to draw an effectiveamount of subcutaneous fluid from the subject through the at least oneformed pathway and subsequently transdermally deliver at least a portionof the permeant through the formed pathway at a desired flux. To thisend, the subcutaneous fluid drawn through the at least one formedpathway can initiate the process of dissolving and/or suspending atleast a portion of the permeant disposed within the matrix andsubsequently can provide a viable diffusion pathway for the permeant totransdermally diffuse back into the subject through at least one formedpathway in the skin. Once the permeant has been transdermally deliveredto a viable skin layer of the subject, the permeant can be activelocally or can be taken up by the circulatory system and distributedsystemically. For example, in one aspect, the permeant can be taken upby the lymphatic system.

In addition to the passive chemical diffusion based driving forcesdescribed herein, it is contemplated that additional permeationenhancers can also be used in combination with the permeant deliverymatrices of the present invention. For example, and without limitation,the delivery matrices of the instant invention can be used incombination with an active force enhancer technology, such as theapplication of sonic energy, mechanical suction, pressure, or localdeformation of the tissues, of which sonophoresis, iontophoresis orelectroporation are included.

Still further, additional electromotive forces can also be applied tothe permeant in order to enhance the transdermal permeant flux of thepermeant through at least one formed pathway in the skin of the subject.The use of electromotive forces can be particularly useful fortransdermal delivery of larger macromolecular agents such as proteins,peptides, and even genes in therapeutic amounts through microporatedskin. Moreover, such active delivery modes can in other aspects be usedwith fewer and/or smaller pathways than are often needed for anequivalent flux via a passive diffusion only system. Thus, in oneaspect, the use of active electromotive forces can thereby reduce thevolume of skin to be ablated, making the system even less invasive forthe user.

To that end, in one aspect, a permeant delivery matrix according to theinstant invention can be configured to provide an electro-osmotic-pump(EOP) assembly. According to this aspect, and as depicted in FIG. 5, amicroporated delivery matrix 20(d) having a top surface and an opposedbottom surface, can further comprise an assembly of one or more firstelectrodes 60 positioned in electrical communication with the topsurface and an assembly of one or more second electrodes 70 positionedin electrical communication with the bottom surface. The electrodeassemblies can be provided by any conventional electrode depositiontechniques know to one of skill in the art, such as, for example,sputtering, electro-deposition, or electro-less deposition. A completecircuit can then be created by placing the first and second electrodeassemblies in selective or controllable electrical communication with avoltage or current source (V). A steady application of a properlypolarized electrical field to the permeant within the microporatedmatrix can induce a build up of permeant in the vicinity of the openingsof the microporated matrix, thus providing a relative boost to thediffusion gradient driven transdermal delivery into a subject.

In still another aspect, an electro-osmotic-pump assembly according tothe present invention can further comprise a third or counter electroderemotely positioned from the delivery matrix and adapted to bepositioned in electrical communication with the skin of a subject. Theincorporation of a third, or counter electrode, can enable theapplication of an electromotive force capable of enhancing the movementof the permeant from the bottom surface of the microporated deliverymatrix laterally to foci coincident with the at least one formed pathwayin the skin of the subject. As will be appreciated, this aspect of theinvention can provide additional transdermal flux efficiency since therewill be essentially zero flux through the intact portions of the skinwhich still have the undisrupted stratum corneum layer and do not have aformed pathway open to the viable layers of the skin.

In use, a three-electrode assembly as described above can be operatedaccording to a selective on-off cycling of the various electrodeassemblies within the electro-osmotic pump assembly. For example, in afirst electro-osmotic pump cycle, the electro-osmotic pump (EOP) can beactivated by completing a circuit between the first and second electrodeassemblies in order to create a relatively high concentration of thebioactive agent in the proximity of the microporous openings in thebottom surface of the delivery matrix. During a second electro-transportcycle, one or both of the first and second EOP electrode assemblies canbe charged with the same polarity as the net charge on the particularbioactive agent to be transdermally delivered. The third electrodeassembly, which can be positioned remotely from the delivery matrix andin communication with the surface of the skin, can then be operated as acounter electrode. In this electro-transport mode, the electro-repulsiveforce exerted on the bioactive agent can actively drive the bioactiveagent into the micropores of the subject.

Of course, it should be appreciated that this electro-transport mode(ETM) and the electro-osmotic-pump mode (EOP) can be modulated in anon-off manner, or in any level between off and maximum intensity. Bykeeping the amount and duration of the ETM within certain exemplarylimits, such as, for example, 10 ms on and 50 ms off, the averagecurrent which will flow through the skin tissues of a subject during ETMcan be kept to a low enough level that any shifts in local pH can beneutralized during the off-time of the ETM by the normal micro-fluidicaction within the skin tissues and the natural diffusion of ions when noelectric field is present. As will be appreciated by one of skill in theart, this can work to establish uniform concentration of all mobilespecies, thus bringing the pH back to its normal physiological state. Assuch, this modulation of on-time to off-time of the ETM can alsoeliminate irritation due to a disruption of the normal pH of the skintissues.

It should be understood that the specific duty cycles of the EOP mode orcycle and the ETM mode or cycle can depend on the particular permeant tobe transdermally delivered and the current levels applied to both theEOP and ETM. Whereas a rough calculation can be made that will ensurethe pH of the viable tissues stays within some predetermined boundary,in practice, these duty cycles can be determined experimentally bysimply placing a small pH sensor under the patch to monitor the effectsof different duty cycles. A further feature of this invention would beto incorporate a pH sensing element into the patch and use the outputgenerated by it as a feedback signal to the system controller such thata closed-loop control circuit is implemented which ensures that the pHis held within the programmed boundaries, regardless ofsubject-to-subject variations in local skin physiology, environmentalfactors, or other forces which may affect the local environment.

With reference to FIG. 6, an exemplary patch assembly further comprisinga three-electrode osmotic pump assembly is depicted. As illustrated, theexemplary device comprises a transdermal patch assembly, comprising amicroporated delivery matrix as previously described herein. Thedelivery matrix is constructed and arranged such that it has a topsurface and an opposed bottom surface. A backing support layer, havingan inwardly facing surface is at least partially connected to the topsurface of the delivery matrix. The microporated delivery reservoircomprises a top surface and an opposed bottom surface. A first electrodeassembly 60 is positioned in electrical communication with the topsurface and a second electrode assembly 70 is positioned in electricalcommunication with the bottom surface. A third or counter electrode 80is remotely positioned from the delivery matrix and adapted to bepositioned in electrical communication with the skin of a subject. Acomplete circuit can then be created between at least any two of thefirst, second and third electrodes by placing at least two of the first,second and third electrode assemblies in selective or controllableelectrical communication with a voltage or current source (notillustrated).

EXAMPLES The following examples are put forth so as to provide those ofordinary skill in the art with a complete disclosure and description ofhow the devices, systems and methods claimed herein are made, performedand evaluated. These examples are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Unless indicated otherwise, parts are partsby weight, temperature is degrees C. or is at ambient temperature, andpressure is at or near atmospheric.

Hydromorphone

FIG. 7 reports the effect of permeant delivery patch thickness on the invitro drug release kinetics for various permeant delivery patches of thepresent invention. Four permeant delivery patches were preparedaccording to the present invention. The four matrices each comprisedethylene vinyl acetate copolymer (EVA). The permeant formulationsdisposed within the EVA matrices comprised hydromorphone HCl (HM) as thebioactive agent and mannitol and propylene glycol (PG) as fillercomponents and were approximately 1.44 cm in area. The first patch had athickness of approximately 1.00 mm and comprised approximately 67 mg ofhydromorphone. The second patch had a thickness of approximately 0.50 mmand comprised approximately 25 mg of hydromorphone HCl. The third patchhad a thickness of approximately 0.44 mm and comprised approximately 22mg of hydromorphone. The fourth patch had a thickness of approximately0.22 mm and comprised approximately 11 mg of hydromorphone HCl.

In vitro tests using each of the four patches were conducted for anadministration period of approximately 24 hours. Using conventionalmeans for analysis, the cumulative hydromorphone HCl release andrelative percentage of hydromorphone HCl release for each of the fourpermeant delivery patches over the 24-hour administration period arereported by the plots depicted in FIG. 7.

FIG. 8 reports the mean pharmacokinetic profile (PK profile) for anexemplary permeant delivery device according to the present inventionthat was tested on the abdomen region of four different hairless ratsubjects. The permeant patch was a film having a thickness ofapproximately 1.4 millimeters and comprised 50 weight percent of anethylene vinyl acetate copolymer having approximately 40% vinyl acetatecomponent as the matrix material. The permeant composition comprised 25weight percent hydromorphone HCl (relative to the total weight percentof the permeant patch) as the bioactive agent and 25 weight percentmannitol (relative to the total weight of the permeant patch) asadditional filler component. The mean serum hydromorphone concentrationin the hairless rats as a function of a 24-hour administration period isreported in FIG. 8.

Fentanyl Citrate

FIG. 9 reports the mean fentanyl citrate serum level PK profile forpermeant delivery patches of the present invention comprising differingconcentrations of fentanyl citrate. In particular, shown is a comparisonof mean fentanyl citrate serum level PK profiles for delivery patchesprepared according to procedures similar to the following for 10%fentanyl citrate.

Preparation of an exemplary permeant delivery patch comprising 10%fentanyl citrate as the bioactive agent: To prepare the patch, mannitolis sieved using a 200 mesh sieve before use.

The patch can then be prepared by charging approximately 3000 mg offentanyl citrate and approximately 18450 mg of mannitol into a vial andallowing the mixture to blend for at least 6 hours. Approximately 8550mg of ethylene vinyl acetate comprised of approximately 40% vinylacetate component can be added to the blended mix of fentanyl citrateand mannitol. The charged materials can be continuously stirred andheated in a temperature controlled container to a temperature in therange of approximately 80 C to 120 C. After the mixture achieves adough-like consistency, the mixture can then be transferred to a backingfilm such as the Scotchpak backing available from 3M®.

Once deposited on the backing material, the dough-like material can becompressed between the backing layer and a protective release linerlayer (such as the 1521 single-sided polyethylene film, also availablefrom 3M®) to provide a patch having a desired thickness. After the patchmaterial has cooled, the resulting film can then be cut to provide apatch having a surface area of, for example, approximately 1 cm². Apatch prepared according to the foregoing procedure can, for example,comprise a concentration of bioactive agent of approximately 3.8 mgfentanyl citrate per patch. Prior to applying the exemplary patch onto atest subject, the protection release layer would first be removed toexpose the bottom surface of the matrix.

FIG. 9 shows that, in one aspect of the present invention, fentanylcitrate can be delivered through micropores in the skin and that thesteady-state level can be controlled by the fentanyl content of thedelivery patch.

Fentanyl Chase For the fentanyl chase study, the abdomen of the hairlessrat was again microporated followed by the application of a film orsolution of interest. The patch (film or solution) was removed atpredetermined specified times (i.e., 12 hours after application) and theadministration site was covered with a subsequent or chase liquidreservoir patch, filled with about 200 uL of saturated fentanyl citratesolution. Blood samples were then removed from the tail vein of thehairless rat (typically 6-10 hours after patch change or 18-22 hoursafter microporation). Serum was separated from the blood samples forfentanyl analysis.

Data generated by such a fentanyl chase study is shown in FIG. 10.Twelve hours after application of one of the formulations (listed on thex-axis) the site was covered with a saturated fentanyl citrate solutionand blood sampling commenced. The y-axis represents the average serumfentanyl levels reached 6-10 hours after application of the fentanylsolution. The control bar represents levels attained 6-10 hours after asaturated fentanyl citrate solution had been applied to freshlymicroporated skin. From the data it is apparent that by covering afreshly microporated site for 12 hours with a film made from solely EVAthe delivery of fentanyl is prevented. The same approximate results wereobtained if the site were covered with a film made from EVA/mannitol orif covered with a saturated mannitol solution. If, on the other hand,the site was first covered with a film containing fentanyl orhydromorphone, then fentanyl levels were observed at approximately 60%and 85% respectively of those obtained for the control.

Insulin

FIG. 11 reports a chart demonstrating the effect of adding polyvinylalcohol (PVA), a water-soluble polymer, to an insulin formulationcontaining tris as a permeability enhancer. The addition of the polymeraffords an extended profile of insulin delivery by controlling releaseof drug and/or permeability enhancer from the film. The matrix scaffoldis comprised of ethylene vinyl acetate (EVA).

FIG. 12 reports a chart demonstrating the effect of adding ethylcellulose (EC), a water-insoluble polymer to an insulin formulationcontaining tris as a permeability enhancer. The addition of the polymeraffords an extended profile of insulin delivery by controlling therelease of drug and/or permeability enhancer from the film. The matrixscaffold is comprised of ethylene vinyl acetate (EVA).

Exenatide

FIG. 13 reports a chart demonstrating the effect of various permeabilityenhancers on exenatide delivery in the hairless rat. Animals weremicroporated on the abdomen and a patch containing a 20 OuL solution ofexenatide (10.5 mg/mL) and the agent of interest (3% w/v) was appliedover the site. A fresh solution was re-applied over the site every fourhours and blood was sampled for exenatide levels over 24 hours. Whiledisodium citrate provided roughly steady levels for the 24 hour period,the use of either succinic acid or maleic acid provided enhanced levels.

FIG. 14 reports a chart demonstrating the effect of succinic acid (SA)and ethyl cellulose (EC) in a formulation designed to achieve extendeddelivery of exenatide over 24 hours. The 30% succinic acid formulationprovides higher Cmax and area under the curve (AUC) relative to aformulation containing 57% disodium citrate (DiNaCitrate). The matrixscaffold is comprised of ethylene vinyl acetate (EVA).

FIG. 15 reports a chart demonstrating the effect of polymer and/orpermeability enhanceres on in vitro exenatide release. The identity orcomposition of the permeability enhancer can be modified to alter thedissolution profile of the films. For example, 30% ethylcellulose-containing films release exenatide at a faster rate than 45%ethyl cellulose-containing films.

FIG. 16 reports a chart demonstrating the effect of permeabilityenhancer composition on the in vitro release of exenatide from exenatidefilms containing ethylene vinyl acetate (EVA) and the permeabilityenhancers of interest. Increasing percentages of disodium citrate havethe effect of slowing the rate of exenatide release from the films.

Pore Permeability Enhancers

FIG. 17 reports the effect of permeability enhancer identity on themaintenance of pore permeability. Polymeric films were prepared with EVAand −70% of the permeability enhancer listed. Hairless rats weremicroporated and the films were placed on the microporated site for 12hours, after which time the polymeric film was replaced with a liquidreservoir patch containing a fentanyl citrate solution and bloodfentanyl levels were monitored. In the absence of any permeabilityenhancer (i.e. films containing 100% EVA only) the fentanyl levelsachieved after application of a fentanyl solution were <5 ng/mL,however, as shown, the inclusion of permeability enhancers producedsignificantly higher fentanyl levels. The pH of the skin at the siteafter final patch removal is shown for reference on the right axis. Itis to be noted that this is simply one non-limiting example of ascreening method for the effect of permeability enhancer identity on themaintenance of pore permeability. Other methods as well as otherpermeability enhancers may be used and tested.

1-63. (canceled)
 64. A method for delivering a permeant through a biological membrane of a subject comprising: a) forming one or micropores in the biological membrane; and b) placing a patch in physical contact with said one or more micropores, wherein said patch comprises: i) a matrix; ii) at least one hydrophilic permeant disposed within the matrix, wherein at least a portion of the hydrophilic permeant can dissolve in biological moisture received from the subject through said one or more micropores; and iii) at least one permeability enhancer disposed within the matrix.
 65. The method of claim 64, wherein the one or more micropores are formed using at least one device from the group consisting of: thermal porators, mechanical porators, laser porators, and hydraulic porators.
 66. The method of claim 64, wherein the one or more micropores are formed using a heat conducting element placed in substantial physical contact with the biological membrane to deliver sufficient energy to the biological membrane to thermally ablate said biological membrane.
 67. The method of claim 64, wherein the one or more micropores are formed using a thin film tissue interface device.
 68. The method of claim 64, wherein the hydrophilic permeant is a bioactive agent.
 69. The method of claim 68, wherein the bioactive agent is a protein drug.
 70. The method of claim 69, wherein the protein drug is exenatide.
 71. The method of claim 69, wherein the protein drug is insulin.
 72. The method of claim 68, wherein the bioactive agent is hydromorphone.
 73. The method of claim 68, wherein the bioactive agent is fentanyl citrate.
 74. The method of claim 64, wherein the permeability enhancer is a pH control agent.
 75. The method of claim 74, wherein the pH control agent is at least one selected from the group consisting of succinic acid, disodium citrate, trisodium citrate, and tris.
 76. The method of claim 74, wherein the pH control agent is succinic acid.
 77. The method of claim 74, wherein the pH control agent is disodium citrate.
 78. The method of claim 64, wherein the matrix comprises at least one polymer.
 79. The method of claim 78, wherein the polymer is a water insoluble polymer.
 80. The method of claim 78, wherein the polymer is a water soluble polymer. 81-82. (canceled)
 83. The method of claim 79, wherein the water insoluble polymer is at least one selected from the group consisting of: ethylene vinyl acetate and ethyl cellulose.
 84. The method of claim 80, wherein the water soluble polymer is at least one selected from the group consisting of: polyethylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone.
 85. The method of claim 64, further comprising a solubility control agent.
 86. The method of claim 85, wherein the solubility control agent is at least one selected from the group consisting of: sodium citrate, sodium chloride and ammonium sulfate.
 87. The method of claim 64, wherein the hydrophilic permeant is delivered to the subject for an administration period ranging from about 5 minutes to about 24 hours. 88-108. (canceled)
 109. The method of claim 68, wherein the bioactive agent is enoxaparin.
 110. The method of claim 64, wherein the hydrophilic permeant is delivered to the subject for an administration period ranging from about 5 minutes to about 12 hours.
 111. The method of claim 64, wherein the hydrophilic permeant is delivered to the subject as a bolus. 